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Review

Unlocking Novel Therapeutic Potential of Angiotensin II Receptor Blockers

by
Filippos Panteleimon Chatzipieris
1,
Kiriaki Mavromoustakou
2,
John M. Matsoukas
3,4,5,6 and
Thomas Mavromoustakos
1,*
1
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece
2
First Cardiology Department, Medical School, National and Kapodistrian University of Athens, Hippokration General Hospital, 11527 Athens, Greece
3
Institute for Health and Sport, Victoria University, Melbourne, VIC 3030, Australia
4
Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
5
NewDrug, P.C., Patras Science Park, 26504 Patras, Greece
6
Department of Chemistry, University of Patras, 26504 Patras, Greece
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(18), 8819; https://doi.org/10.3390/ijms26188819
Submission received: 22 July 2025 / Revised: 5 September 2025 / Accepted: 8 September 2025 / Published: 10 September 2025

Abstract

Pharmaceutical companies keep producing novel drugs and drug treatments for improving the life of every sick individual, most often following a pattern; a specific drug for a specific condition. Evidence suggests that different medications can have a positive effect on different pathological conditions. The full potential of existing therapies can be revealed through drug repurposing—also referred to as drug repositioning, reprofiling, or re-tasking—which involves identifying new therapeutic uses for approved or investigational drugs beyond their original indications. One significant target in this context is the renin–angiotensin–aldosterone system (RAAS), a crucial regulator of blood pressure and fluid homeostasis, and a central focus in the treatment of chronic cardiovascular conditions such as arterial hypertension (AH) and heart failure (HF). Interestingly, novel investigations show that AT1 antagonists (sartans) are able to broaden their therapeutic scope and potentially combat other diseases such as neurodegenerative diseases, cancer, and osteoarthritis, and even help people with methamphetamine and opioid addiction.

1. Introduction

1.1. Introducing Drug Repurposing

Drug repurposing (repositioning, reprofiling, re-tasking, rediscovery, or rescue) is a method used to discover new therapeutic applications for approved or investigational drugs beyond their original medical purposes [1,2]. This approach provides several benefits compared to creating a completely new drug for the same condition. A repurposed drug has an advantage because it has been found safe in preclinical and early human trials [3,4]. As a result, they are less likely to fail due to safety concerns in later efficacy trials. Also, the drug development timeline can be shortened since much of the preclinical testing, safety evaluation, and sometimes formulation work has already been carried out [5,6]. Finally, the required investment is generally lower, although the amount can vary significantly based on the development stage and process of the repurposing candidate. Combined, these benefits can lead to a quicker and less risky return on investment when developing repurposed drugs, with overall lower costs after considering potential failures. Most importantly, repurposed drugs might uncover new targets and biological pathways that could be explored further [7,8].

1.2. RAAS Physiology

The renin–angiotensin–aldosterone system (RAAS) is a key regulator of vascular tone and fluid homeostasis. Juxtaglomerular cells release renin which initiates the conversion of angiotensinogen to angiotensin I (Ang I) which is then converted to angiotensin II (Ang II) by the angiotensin-converting enzyme (ACE) and other enzymes [9]. Ang II acts predominantly via angiotensin II type 1 (AT1) receptors to raise blood pressure through vasoconstriction, sympathetic activation, and enhanced sodium retention. Ang II also stimulates aldosterone secretion, further promoting sodium reabsorption [10]. Chronic AT1 activation contributes to vascular inflammation, hypertrophy, and fibrosis. In the opposite direction, AT2 receptor engagement counteracts these effects through vasodilation and natriuresis. In particular, in the RAS, angiotensin-converting enzyme 2 (ACE2) cleaves vasoconstrictor Ang II to delete Phe at position 8 and produce vasodilator heptapeptide Ang (1–7), counterbalancing the toxic axis ACE1/Ang II, maintaining homeostasis, and controlling blood regulation. An example of the beneficial effect of the protective Ang (1–7)/MAS (MAS proto-oncogene) axis in the renin–angiotensin system is its heptapeptide constituent Alamantine which reverses vascular dysfunction [11]. Pharmacologic blockade of RAAS offers a therapeutic strategy across multiple cardiovascular and renal conditions [12].

1.3. Multi-Target Directed Ligand (MTDL) Approach

Targeting several pathways at once has proven effective in improving drug performance and combating resistance, particularly in complex diseases. From Alzheimer’s to cancer, more and more data show that most of the publicly known diseases are actually multifactorial. The strategy of “one molecule for one drug target”, while having shown improvements in the lives of many people worldwide, is outdated. Focus should also be given to the development of Multi-Target Directed Ligands (MTDLs) with the simplest example being dual inhibitors. MTDLs are rationally designed to act on several targets and have become a widely accepted approach in drug discovery [13,14,15,16].
Thus, the focus of this review will be on the study of molecules acting as ARBs and their potential use in other pathological conditions as well as their ability to inhibit multiple molecular targets. Moreover, we will present our laboratory’s work on the development of novel AT1 inhibitors and dual inhibitors for the treatment of multiple diseases. The graphic representation in Figure 1 summarizes the topics covered in this review article.

2. Establishing Drug Repurposing: The Example of Sildenafil

Newly developed drugs do not enter the market until all regulatory conditions have been fulfilled [17]. For a drug candidate to be established as a treatment for a certain disease, much time (10–15 years) [18], money (roughly USD 1.8 billion until its entry to the market) [19], and effort is needed. The first step is to design and synthesize the compound of interest. Testing its in vitro and in vivo activities is the second step of drug development, along with the examination of its toxicity effects [20,21]. By the time it proceeds to clinical trials, a significant amount of money has been consumed for the purchase of resources, while many experimental animals have also been used, which is not ideal from a bioethical point of view. A further rise in costs is observed when scaling up the production [2]. Due to these limitations, the research community draws its attention to established drugs, which have already passed the standards set by the strict regulatory authorities and have been deemed safe for use. For a repurposed molecule, existing safety, preclinical, and efficacy data are already available, allowing researchers to make well-informed decisions at every stage of drug development [4,22]. Investigational molecules that do not demonstrate efficacy for their initial indication are also promising candidates. Such compounds can be redirected toward new indications and ultimately developed into effective therapies, a strategy especially valuable for rare diseases, which pose substantial challenges in terms of diagnosis, treatment, and limited resources [23,24]. This strategy helps mitigate the rising costs of drug development, thereby reducing patients’ out-of-pocket expenses and ultimately lowering the overall cost of therapy [4,22,24,25].
The best example of a drug being developed to regulate one condition and ending up more well-known and profitable to another is sildenafil (Viagra). In 1986, Pfizer established a project team of scientists in Sandwich, UK to develop a selective phosphodiesterase-5 (PDE5) inhibitor and assess its preclinical pharmacological properties. The goal was simple: the inhibition of PDE5, a selective catalyst in the breakdown of cyclic guanosine monophosphate (cGMP), shall result in the excess of this molecule in the body, which will subsequently promote the initiation of a cascade of reactions that ultimately decreases intracellular calcium levels, thereby promoting relaxation of the smooth muscle. Thus, it would be a mixed dilator of arteries and veins by relaxing vascular smooth muscle, which lowers peripheral vascular resistance and cardiac preload while improving blood flow to ischemic heart tissue. This would have an anti-anginal effect. In 1992, when given doses up to 75 mg three times daily for 10 days, some volunteers experienced side effects such as headaches, flushing, indigestion, and muscle pain. Additionally, some reported penile erections as an unexpected effect [26]. Based on observations and studies of Ignarro et al. [27] in the early 1990s, where it was found that nitric oxide (NO) acts as the neurotransmitter released from cavernous nerves during sexual arousal, triggering cGMP production and ultimately leading to an erection [27], clinical trials began in late 1993 for patients with erectile dysfunction [26] and the rest is history.
Success stories only begin with the example of sildenafil. Table 1 presents several successful cases, showing both their original indications and, in most instances, their newly approved indications.
Sildenafil is the best example of retrospective clinical analysis leading to repurposing (or rescue if the drug had otherwise failed for its primary indication) of a candidate molecule. Typically, a drug-repurposing strategy involves three steps before advancing a candidate drug through the development pipeline. The first step is identifying a potential molecule for a specific indication, also known as hypothesis generation. The second step involves assessing the drug’s mechanism of action using preclinical models. The third step is to evaluate the drug’s efficacy in phase II clinical trials, provided there is adequate safety data from phase I studies conducted for the original indication. Among these three steps, the first—accurately identifying the appropriate drug for a specific indication with high confidence—is crucial. This is the stage where modern methods for hypothesis generation can be particularly valuable. These systematic strategies are categorized into computational and experimental approaches, and their combined use is becoming increasingly common to enhance effectiveness. The most frequently employed computational methods include retrospective clinical analyses, molecular docking, signature matching, genetic association studies, pathway mapping, and the use of emerging data sources, while experimental approaches such as binding assays to identify relevant target interactions and phenotypic screenings are also employed [2,22,143].
Although drug repurposing as a strategy is advantageous due to its cost-effectiveness and ability to shorten the drug-discovery timeline, it is important to carefully consider the various factors that may influence its implementation. A major barrier is the pharmaceutical industry’s limited focus on financially rewarding diseases, which reduces opportunities for drug repurposing in orphan diseases and neglected tropical disorders. In addition, repurposed drugs face legal challenges such as limited patent protection and difficulties in conducting clinical trials, both of which reduce their chances of successful development. It is crucial to address further challenges, including the risk of false-positive signals during data mining and the susceptibility of hypothesis validation to bias and confounding factors. The lack of clear regulatory guidance represents an additional obstacle in advancing drug-repurposing efforts [144]. Moreover, the repurposed drugs might have implications with off-target interactions, resulting in adverse effects. For instance, sildenafil can cause headache, flushing, nasal congestion, dyspepsia, and a slight decrease in systolic and diastolic blood pressure. Moreover, combining the drug with alcohol can lead to cerebrovascular hemorrhage; a rare fatal side effect [145].

3. Repurposing Angiotensin II Receptor Blockers (ARBs)

ARBs are used as first-line treatment, with different class indications, in hypertension, heart failure, post-myocardial infarction, chronic kidney disease and for the prevention of cardiovascular events, particularly in individuals with atherosclerotic coronary artery disease (CAD) or type 2 diabetes with damage to at least one organ [146].

3.1. Hypertension

Pioneer research on angiotensin and the mechanism that triggers hypertension and blood pressure has revealed a Charge Relay System (CRS) mechanism, analogous to serine proteases, involving the three aromatic residues tyrosine, Histidine, Phenylalanine and C terminal carboxylate, resulting in a tyrosinate anion [147,148]. In particular, a tyrosine hydroxylate is formed by delocalisation of the negative charge originating from the Phe carboxylate of angiotensin II (Ang II), through CRS, and activates the AT1 receptor triggering blood pressure, vascular dysfunction, and congestive heart failure. The important role of hydroxyl in Ang II was demonstrated by methylation of tyrosine hydroxyl resulting in loss of agonist activity, as shown in Sarmesin analogs which exhibit competitive antagonist activity [149,150].
Elevated blood pressure and hypertension (HT) are conditions associated with many health issues, especially cardiovascular problems such as heart disease, stroke, and heart failure, with cardiovascular disease being the leading cause of mortality worldwide [151]. From 2025 to 2050, cardiovascular disease prevalence is expected to rise by 90.0%, with cardiovascular deaths projected to reach 35.6 million in 2050, up from 20.5 million in 2025 [152,153]. Globally, high blood pressure is responsible for roughly 54% of strokes and 47% of coronary heart disease cases [154].
The major classes of medications for blood pressure control are angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), dihydropyridine calcium channel blockers (CCBs), diuretics (thiazides and thiazide-like diuretics), and beta-blockers. According to the European Society of Cardiology guidelines, ACE, ARBs, CCBs, and diuretics are recommended as first-line treatment [155,156].

3.2. Heart Failure

Heart failure (HF) is a clinical syndrome caused by structural and/or functional heart diseases that increase intracardiac pressure and/or impair cardiac output, affecting approximately 1–2% of adults [157,158]. In clinical practice, it is well-known that the RAAS plays a pivotal role in heart failure (HF). Unlike ACE inhibitors, ARBs act downstream by blocking Ang II from attaching to AT1 receptors. This is believed to cause Ang-II to bind more to AT2 receptors, potentially providing greater antifibrotic benefits than ACE inhibitors. However, clinical evidence supporting the effectiveness of ARBs in heart failure patients is less robust compared to that for ACE inhibitors and thus ARBs are recommended in patients who are intolerant to ACEIs or ARNI (sacubitril/valsartan) [159]. ARNI is a combination of ARBs and neprilysin inhibitors and is recommended in patients with HF who remain symptomatic despite the optimal treatment with ACEIs or ARBs. According to the European Society of Cardiology (ESC) 2023 guidelines, ARBs are recommended for patients with Heart Failure with Reduced Ejection Fraction (HFrEF) (Class I) and Heart Failure with Mid-Range Ejection Fraction (HFmrEF) (Class IIa) who are intolerant to ACEIs and ARNI [160].

3.3. Chronic Kidney Disease

Globally, in 2021, more than 850 million people were affected by kidney disease, approximately twice the number of people living with diabetes (422 million) and 20 times the global prevalence of cancer (42 million). According to the KDIGO (Kidney Disease: Improving Kidney Outcomes) 2024 guidelines, ARBs and ACE are recommended for people with chronic kidney disease (CKD). Specifically, they are recommended for patients with CKD and severely increased albuminuria (1B), for those with moderately increased albuminuria (2C), and for individuals with moderate-to-severe albuminuria and diabetes (1B) [161]. In summary, from a mechanistic point of view:
  • Ang II acting via AT1R activates signaling cascades—MAPK (Mitogen-activated protein kinase)/ERK (Extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase), STAT (Signal transducer and activator of transcription), NF-κB (Nuclear factor kappa light chain enhancer of activated B cells), and Activator Protein (AP)-1—to drive fibrosis, inflammation, cell proliferation, and proteinuria in CKD. AT2 receptors counter these effects via inhibitory signaling [162];
  • Ang II as a renal growth factor, stimulates proliferation of mesangial/tubular cells and fibroblasts, promoting extracellular matrix (ECM) accumulation and Transforming Growth Factor (TGF)-β induction. RAS blockade (ACE inhibitors, AT1R antagonists) prevents proteinuria, fibrosis, and inflammatory infiltration [162]; and
  • On podocytes—a key filtration-cell type—Ang II causes cytoskeletal disruption, ROS production, and apoptosis, driving podocytopathy and glomerulosclerosis. RAS blockade protects structurally and functionally [163].

3.4. Acute Coronary Syndrome

Cardiovascular disease (CVD) remains the leading cause of death and disability globally and in many cases, acute coronary syndrome (ACS) serves as the initial clinical presentation of CVD [164,165,166]. Secondary prevention following ACS is essential to improve quality of life and reduce both morbidity and mortality. It should be initiated as soon as possible after the initial event. ARBs are recommended in patients with intolerance of ACE inhibitors after ACS with HF symptoms, Left Ventricular Ejection Fraction (LVEF) < 40%, hypertension, and/or CKD [167]. In summary, from a mechanistic point of view:
  • Systemic and local RAS activation drives remodeling and worsens outcomes post–MI (myocardial infarction) [168];
  • Ang II activates NADPH (Nicotinamide Adenine Dinucleotide Phosphate) oxidase, causing oxidative injury and atherosclerosis [169];
  • Ang II, AT1R, and ACE co-localize in plaques, promoting interleukin IL-6 release and instability [170];
  • ARBs post-MI upregulate ACE2/Ang (1–7)/MAS (MAS proto-oncogene) and inhibit fibrosis [171]; and
  • The ACE2/Ang (1–7)/MAS axis mitigates ischemia–reperfusion injury (IRI) via anti-inflammatory, antioxidant signaling [172].

3.5. Alzheimer’s Disease

Alzheimer’s disease (AD) is a well-known progressive form of neuronal cell degeneration, which influences older humans and is estimated to affect 139 million people by 2050 [173]. Although AD is a multifactorial disease and the most prevalent type of dementia among older adults, its main cause is still not fully understood. The prevailing theory for the pathophysiology of Alzheimer’s is the amyloid theory. In this theory, the amyloid precursor protein (APP) is being hydrolyzed by β-secretase and γ-secretase to yield the insoluble amyloid-beta (Aβ) [174]. This is then accumulated in the brain to finally form the Aβ plaques (senile plaques). Elevated levels of Aβ protein are toxic to mature neurons, leading to the shrinking of dendrites and axons, which eventually results in neuronal death. Beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) inhibitors, designed to decrease Aβ levels, have been tested for many years; however, none have successfully passed clinical trials. In fact, one of them (Lanabecestat) was able to lower cerebrospinal fluid (CSF) Aβ levels by up to 75%. However, on 12 June 2018, phase II/III trials of Lanabecestat were discontinued due to a lack of efficacy. The same happened to many other inhibitors of the same class, as they had very minimal effects on protecting cognitive decline, in some cases worsening it [175,176,177]. Thus, other molecular targets should be determined for the improvement of Alzheimer’s pathology.
The cerebrovascular aspect of Alzheimer’s disease has frequently been overlooked because of the traditional separation between vascular dementia and AD pathology—an outdated distinction that no longer holds [178,179]. Recently, emerging preclinical and clinical evidence has associated the brain renin–angiotensin system (RAS) to AD pathology. Consequently, several elements of the brain RAS—such as angiotensin II type 1 (AT1), angiotensin IV (AT4), and MAS receptors—have been found to be altered in both AD patients and mouse models. Together, the alterations seen in the RAS are believed to play a role in several key neuropathological features of AD, such as neuronal damage, cognitive decline, and vascular problems. Growing evidence has also shown that antihypertensive drugs targeting the RAS—especially angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs)—can help delay the onset and progression of Alzheimer’s disease [180,181]. Moreover, these drugs can have a positive effect on vascular dementia [182]. In a clinical study of non-hypertensive individuals with prodromal Alzheimer’s disease, candesartan was found safe and appeared to reduce brain amyloid biomarkers, improve subcortical brain connectivity, and support cognitive function. These results indicate that candesartan could play a significant therapeutic role in Alzheimer’s disease and highlight the need for further research, given the current lack of effective treatment options for this condition [183]. In summary, from a mechanistic point of view:
  • Ang II via AT1R increases amyloid-β (Aβ) by upregulating APP mRNA, β-secretase activity, and presenilin expression; it also promotes tau phosphorylation and reactive oxygen species (ROS) generation [184];
  • AT1R activation contributes to neuroinflammation, oxidative stress, Aβ accumulation, all implicated in AD pathogenesis [185];
  • Overactivation of the Ang II/AT1R axis leads to blood–brain barrier (BBB) disruption, and neurotoxicity [186],
  • Brain aging shows an imbalance favoring renin/ACE1/Ang II/AT1R activation, contributing to cognitive decline and neuroinflammation [187];
  • Ang II/AT1R-mediated vasoconstriction impairs neurovascular coupling, undermining cerebrovascular function [188]; and
  • Hyperactivation of AT1Rs has been shown to induce NADPH oxidase activity that leads to ROS production, thereby prompting oxidative stress, a pathway activated by Aβ in AD [180].

3.6. Parkinson’s Disease

Parkinson’s disease (PD) is the most common movement disorder and ranks as the second most widespread neurodegenerative disease. Although Parkinson’s disease (PD) has traditionally been seen mainly as a motor disorder marked by bradykinesia, muscle stiffness, resting tremors, and balance problems, it also includes non-motor symptoms that significantly impact patients’ quality of life. Neuropsychiatric symptoms, such as mood changes, cognitive decline, and psychosis, are the most common among these. Besides reducing quality of life, they also increase the caregiver’s workload and raise the likelihood of institutionalization. Depression is the most common mood disorder, impacting up to 50% of patients as the disease progresses, while anxiety—though frequently occurring alongside depression—has received comparatively less research attention [189]. Evidence suggest that the local nigrostriatal RAAS likely plays a role in regulating dopaminergic neurotransmission, blood flow, and inflammatory responses [190]. The intricate interaction between angiotensin (Ang) and dopamine (DA) relies on the balance of D1, D2, AT1, and AT2 receptors. While the D1 receptor promotes Ang production, the D2 receptor inhibits it. In the same way, AT1 receptors increase DA tone, whereas AT2 receptors decrease it. Notably, PD patients exhibit reduced Ang II binding in the basal ganglia, but it is uncertain if this is a cause or an effect of the neurodegeneration seen in PD. In animal models of PD, neuroprotective effects have been demonstrated with the angiotensin-converting enzyme (ACE) inhibitors captopril and perindopril, as well as the AT1 receptor antagonists losartan, candesartan, and telmisartan. These effects seem to be driven by a decrease in the excessive production of reactive oxygen species (ROS). In a proof-of-concept, randomized, double-blind, crossover study involving PD patients, perindopril enhanced the effects of levodopa without causing dyskinesias. A cohort study in hypertensive patients suggested that ACE inhibitors may reduce the risk of developing PD. The RAS represents a promising target for both symptomatic and neuroprotective therapies in PD. Further research involving PD animal models and patients is needed [190,191,192]. In summary, from a mechanistic point of view:
  • Ang II induces dopaminergic neuron apoptosis via NADPH oxidase–mediated ROS [193];
  • Overactivation of Ang II/AT1R exacerbates neurodegeneration in PD models [194];
  • Brain RAS–dopamine dysregulation promotes neuroinflammation and degeneration [195]; and
  • Local RAS in substantia nigra increases vulnerability to degeneration [195].
Certain ARBs possess higher blood–brain barrier (BBB) penetration when compared to others. For instance, losartan, olmesartan, eprosartan, and irbesartan do not cross the BBB, while telmisartan and candesartan are able to cross it. The reason for this is due to their lipophilicity values (logP). Specifically, the logP values are as follows: losartan (1.19) and its active metabolite EXP3174 (−2.45) [196], olmesartan (4.31) [197], eprosartan (3.9) [198], irbesartan (4.56) [199], telmisartan (5.9) [200] and candesartan (6.2) [201]. Thus, it can be deduced that since telmisartan and candesartan have the greater lipophlicity, it is a lot easier for them to cross the blood–brain barrier (BBB). In animal studies, ARBs have been shown to safeguard against impaired cerebral blood flow, neuroinflammation, and neuronal injury. BBB-permeable ARBs may therefore offer particular advantages, as they can penetrate the brain parenchyma to exert direct neuronal effects. In addition to regulating sympathetic activity and hormone production, the brain RAS also influences microglial activation, oxidative stress, cognition, memory, and anxiety-related behavior [202], thus showing salutary effects on cognition and cerebrovascular disease, as well as Alzheimer’s disease (AD) neuropathology. A meta-analysis found that in a large, international, and cognitively intact sample, the use of BBB-crossing ARBs was linked to better memory recall over 3 years of follow-up compared with their non-BBB-crossing counterparts [203].

3.7. Anxiety

Recent studies indicate that local RAS circuits in the brain influence cardiovascular regulation, anxiety (AT), depression, and memory consolidation, with disruptions associated with Alzheimer’s, Parkinson’s, and other neurodegenerative disorders. Bordet et al. [204] performed a clinical study where twelve patients were treated with ARBs and 42 with ACE inhibitors (ACEIs). ARB-treated patients had lower State-Trait Anxiety Inventory (STAI) scores than those on ACEIs or drug-free at baseline and during the follow-up. None of the drugs had an impact on depression scores during the study [204]. In summary, from a mechanistic point of view:
  • Overactivation of the RAS—particularly through AT1R—drives HPA (Hypothalamic–Pituitary–Adrenal) axis hyperactivity, resulting in anxiety-like behaviors. In contrast, AT1R blockers exert anxiolytic effects by normalizing RAS and HPA activity [205],
  • Ang II via AT1R is localized to stress-sensitive brain regions (e.g., hypothalamus) and has been shown to stimulate CRH (Corticotropin-releasing hormone) production, AVP (arginine vasopressin) release, and adrenal catecholamine output, thereby amplifying stress responses [206]; and
  • Stress-induced high Ang II levels cause anxiogenesis via AT1R, and AT2R appears to mediate anxiolytic effects. This suggests that AT2R agonism may counterbalance AT1R-driven anxiety [207].

3.8. Cancer Glioma

In cancer therapy, Konain et al. [208] found that AT1 antagonists showcase strong anticancer potential for glioma. Glioma (GC) is the most common and aggressive type of brain tumor and ranks among the deadliest forms of cancer. Among many abnormally expressed genes, the AT1 receptor is reported to be increased in glioma and linked to aggressive tumor characteristics and disease progression. Thus, the research team performed docking studies to eleven FDA approved ARBs and the drug with the highest docking score was selected for in vitro experimentation. In vitro growth inhibitory assays on patient-derived glioma cell lines showed that telmisartan, at a concentration of 45 ± 0.06 μM, could suppress 50% of the malignant glioma U87 cell population, while PCR (Polymerase Chain Reaction) assays showed that AT1 expression in the untreated sample was high reinforcing the role which exhibits the AT1 receptors on glioma. The results of this study indicate that telmisartan effectively inhibits AT1 expression in glioma cell lines [208]. A phase I clinical trial, where patients with glioblastoma are treated with a combination of RAS modulators, showed that the treatment was well tolerated with low side-effects, preserves the quality of life and performance status of the patients, and may lengthen survival time [209]. Candesartan and other sartans manifest their activity through warhead anionic tetrazolates or carboxylates which bind and block the activity of positive arginines that trigger SARS-CoV-2 [210] and other arginine-based diseases such as glioblastoma [211,212]. ARBs and, in particular, bisartans bearing two tetrazoles, are promising candidates to be explored for the treatment of glioblastoma. In summary, from a mechanistic point of view:
  • Glioblastoma cells express renin, angiotensinogen, renin receptor, ACE, AT1R, AT2R, and renin inhibition induces apoptosis [213];
  • Losartan decreases glioma growth, angiogenic factors, increases apoptosis [214];
  • In a rat glioblastoma (C6 glioma) model, Ang (1–7) inhibited the JNK (c-Jun N-terminal kinase) pathway, which is activated by GBM and known to disrupt tight junction proteins. Blocking JNK preserved endothelial junction integrity, reduced vascular leak, and limited tumor-induced edema [215].

3.9. Pathogenic Inflammation

Pathogenic inflammation (PI) is typically triggered by infections, which stimulate the release of pro-inflammatory mediators like tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and nitric oxide. While infection is the primary cause of inflammation, it has also been shown that danger signals originating from the host or the environment can provoke sterile inflammation. Inflammasomes are protein complexes within the cytosol that detect pathogen infections and various sterile danger signals, triggering the onset of inflammatory diseases and inflammation-associated diseases such as cardiovascular disease, diabetes, and obesity. Of the known inflammasomes, the NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome reacts not only to pathogen infections but also to sterile danger signals originating from the host or environment. Therefore, targeting the NLRP3 inflammasome has become a highly desirable drug target to treat a wide range of human diseases. Candesartan is an angiotensin II receptor antagonist widely used as a blood pressure-lowering drug. Lin et al. [216] showed that candesartan effectively suppressed the NLRP3 inflammasome and pyroptosis in macrophages. Their mechanistic study found that candesartan reduced the expression of NLRP3 and proIL-1β by inhibiting NF-κB activation and decreasing phosphorylation of ERK1/2 and JNK1/2. Additionally, it lessened mitochondrial damage and blocked NLRP3 inflammasome assembly by preventing NLRP3 from binding to protein kinase R (PKR), NIMA-related kinase 7 (NEK7), and apoptosis-associated speck-like protein containing a CARD (ASC). Furthermore, candesartan partially inhibited IL-1β secretion by promoting autophagy. These findings suggest that candesartan possesses broad anti-inflammatory properties and could potentially be repurposed to treat inflammatory diseases or complications related to NLRP3 [216]. A meta-analysis of randomized controlled trials found that ARBs significantly reduced levels of inflammatory markers such as C-reactive protein (CRP), IL-6, and TNF-α [217]. The relationship between angiotensin receptor blockers (ARBs), experimental auto-immune encephalomyelitis (EAE), and multiple sclerosis (MS) has been increasingly explored in recent research. ARBs exhibit anti-inflammatory, neuroprotective, and immunomodulatory properties, making them candidates for repurposing in neuroinflammatory conditions like multiple sclerosis [218,219]. Myelin Basic Protein (MBP) antigens, linear and cyclic, known to contain many arginines, have been extensively studied by us to investigate cytokine secretions in peripheral blood mononuclear cells (PBMC) in multiple sclerosis patients [220] and structural requirements for the binding of MBP peptides to the Major Histocompatibility Complex Class II molecule (MHC II) [221]. The abundant content of basic arginines in MBP (total 19 residues) makes it an attractive peptide to investigate the effects of ARBs and bisartans containing warhead anionic tetrazoles that strongly bind to arginines [222].

3.10. Candidosis

Candidosis (CS) is a common opportunistic infection that can present in various clinical forms, including localized infections in the mouth. Medications targeting the renin-angiotensin system inhibit secreted aspartic proteases produced by Candida albicans. Preclinical studies by Lara et al. [223] showed that these antihypertensive medications could be repurposed to disrupt the metabolism and formation of Candida biofilms, which are commonly linked to clinical candidosis, including oral localized forms like denture stomatitis. Biofilms were exposed to losartan or aliskiren (for comparison) for 24 h. Both drugs decreased fungal viability at all concentrations [223]. No human trials have yet been performed for the treatment of Candidosis.

3.11. Fibrosis

Research also offers strong support for the anti-fibrotic effects triggered by activating the AT2 receptor of the RAAS. Stimulation of the AT2 receptor, like when the AT1 receptor is inhibited, has been shown to prevent fibrosis (FS) development in organs such as the lungs, heart, blood vessels, kidneys, pancreas, and skin. In the lungs, AT2 receptor activation even reversed established fibrosis [180,213,224]. From a mechanistic point of view:
  • Ang II acts through AT1R leading to TGF-β/Smad (Suppressor of Mothers against Decapentaplegic) activation, ROS, inflammation [225];
  • Ang (1–7), acting through the MAS receptor, inhibits fibrosis, reduces inflammation, restores tissue integrity [226]; and
  • In liver fibrosis, AT2R is upregulated and exerts antifibrotic effects by inhibiting the IRE1α-XBP1 (Inositol-Requiring Enzyme 1 alpha-X-Box Binding Protein 1) pathway [227].
There are ongoing clinical trials to assess the efficacy of ARBs in reducing fibrosis in conditions such as sickle cell disease (NCT05012631), aortic stenosis (NCT04913870), and acute kidney injury (AKI) (NCT05272878). The effect of angiotensin-blocking agents on liver fibrosis in patients with hepatitis C has also been evaluated by Corey et al. [228]. Patients with hepatitis C and hypertension exhibit greater fibrosis compared to those without hypertension. Among hypertensive patients, those treated with angiotensin-blocking agents showed reduced fibrosis relative to untreated patients. These findings suggest that hypertension, potentially via the renin–angiotensin system, contributes to fibrosis development and indicate a beneficial role for angiotensin II blockade in hepatitis C–related fibrosis [228].

3.12. Tissue Fibrosis in Systemic Sclerosis

Tissue fibrosis in systemic sclerosis (TFSSc) results from an excessive buildup of extracellular matrix components produced by fibroblasts in skin lesions. Angiotensin II, a vasoconstrictor peptide, is known to promote fibrosis by stimulating extracellular matrix production. Kawaguchi et al. [229] confirmed this fact and found that abnormal production of Ang II may contribute to tissue fibrosis by causing excessive extracellular matrix production in SSc dermal fibroblasts. This implies that targeting the AT1 receptor with antagonists could offer a new approach for treating tissue fibrosis in SSc patients [229]. A clinical study by Dziadzio et al. [230] was conducted to compare the efficacy and tolerability of losartan, with nifedipine for the treatment of primary and secondary Raynaud’s phenomenon (RP). The tolerability of short-term treatment of RP with losartan was confirmed, and the data suggested its clinical benefit. Further evaluation of this drug as a long-term treatment for SSc-associated RP should be considered, since it may have additional disease-modifying potential [230].

3.13. Diabetic Peripheral Neuropathy

Moreover, Iwane et al. [231] conducted clinical and preclinical studies to test whether pharmacological inhibition of the angiotensin system would prevent diabetic peripheral neuropathy (DPN) accompanying type 2 diabetes mellitus (T2DM). In the clinical study, the enrolled 7464 patients were divided into three groups receiving ACEIs, ARBs and the others (non-ACEI, non-ARB antihypertensives). Bonferroni’s test indicated significantly later DPN development in the ARB and ACEI groups than the other groups (receiving non-ACEIs and non-ARBs antihypertensives). The results suggests that pharmacological inhibition of the angiotensin system is beneficial to prevent DPN accompanying T2DM [231]. From a mechanistic point of view:
  • Spinal Ang II/AT1R signaling drives neuropathic pain via p38 MAPK; blocked by losartan [232];
  • ACE inhibition in diabetic rats prevents nerve dysfunction and promotes endoneurial angiogenesis [233]; and
  • Ang II–driven ROS via NADPH oxidase confirms broader neurotoxicity of Ang II/AT1R pathway [234].

3.14. Inflammatory Bowel Diseases

Inflammatory bowel diseases (IBDs), such as Crohn’s disease (CD) and ulcerative colitis (UC), are long-lasting conditions affecting the gastrointestinal tract, characterized by repeated episodes of inflammation. Current treatments for IBD are not curative and fall short in areas such as preventing fibrosis. Medications targeting the renin–angiotensin system (RAS) not only lower blood pressure but also have anti-inflammatory and antifibrotic effects, making them a cost-effective option for managing inflammation and fibrosis in the gut. While RAS inhibitors have shown promise in preventing and easing colitis in preclinical studies, evidence from human trials remains limited. According to Salmenkari et al. [235] retrospective studies of IBD patients treated with ACEIs or ARBs have shown encouraging results, including milder disease progression, fewer hospitalizations, and reduced corticosteroid use. However, prospective studies are necessary to confirm the effectiveness of these promising drugs in treating IBD [235]. Mechanistically:
  • Ang II activates the local RAS leading to the activation of JAK2/STAT1/3, elevated TH1/TH17 (T helper 17) T-cell responses, and IEC apoptosis [236];
  • Ang (1–7)/MASR reduces signaling [p38/ERK/Akt (Protein kinase B)] [237].
Jacobs et al. [238] performed a clinical trial where rates of IBD-related hospitalizations, surgeries, and corticosteroid use were retrospectively assessed in two groups. In the first, 111 IBD patients on an ACEI or ARB were compared 1:1 with matched nonusers based on sex, age, diagnosis, disease location, and hypertension status. In the second, outcomes in 130 IBD patients were compared before and during ACEI/ARB treatment. The results indicated that IBD patients treated with ACEIs or ARBs experienced fewer hospitalizations, surgeries, and corticosteroid courses compared to matched controls. However, no differences in outcomes were observed when patients were compared to their own status prior to ACEI/ARB therapy [238].

3.15. Marfan Syndrome

Marfan syndrome (MS) is a genetic disorder typically caused by harmful mutations in the fibrillin-1 (FBN1) gene, leading to gradual enlargement of the aortic root. If left untreated, this aortic dilation can result in life-threatening aortic dissection, occasionally occurring in early adulthood. Based on a meta-analysis by Pitcher et al. [239], in individuals with Marfan syndrome who had not undergone aortic surgery, ARBs reduced the rate of aortic root Z score enlargement by roughly half, even in those also taking beta-blockers. The impact of beta-blockers was comparable to that of ARBs. Assuming additive effects, starting combination therapy with both ARBs and beta-blockers at diagnosis could further reduce the rate of aortic enlargement compared to either treatment alone. If sustained over several years, this approach is expected to delay the need for aortic surgery [239]. From a mechanistical perspective:
  • AT1R blockade (losartan) in MS mice prevents aneurysm, reverses pathology via TGF-β/Smad suppression [240];
  • AT2R plays a pivotal role for full therapeutic effect; required for ERK inhibition [241];
  • Losartan restored proper muscle regeneration in fibrillin-1–deficient mice by antagonizing TGF-β. This demonstrates that AT1R blockade alleviates systemic manifestations of MS (e.g., myopathy, lung architecture defects), not only vascular issues [242]; and
  • Ang II/AT1R signaling activates ERK1/2 pathways and TGF-β/Smad, driving extracellular matrix degradation and aneurysm formation [243].

3.16. SARS-CoV-2

Furthermore, ARBs and ACEIs have been reported to protect hypertensive patients infected with SARS-CoV-2. Renin–angiotensin system (RAS) inhibitors decrease excess angiotensin II levels while increasing antagonist heptapeptides like alamandine and aspamandine, which help counteract angiotensin II and promote homeostasis and vasodilation. Comprehensive studies have shown that ARBs influence the renin–angiotensin system (RAS) by increasing the levels of the ACE2 enzyme more than other hypertension medications. This is especially significant because ACE2 serves as the entry point for SARS-CoV-2 in the nasopharynx, lungs, and heart cells. Their size, polarity, charge, and receptor selectivity make these drugs well-suited for maintaining homeostasis, suggesting they could be promising therapeutic agents against SARS-CoV-2 infection. ACE2 enzyme, which transforms harmful Ang II into the beneficial peptides Ang (1–7) and alamandine, helps to maintain balance while simultaneously preventing SARS-CoV-2 from entering through ACE2 [244]. A phase III clinical trial with the code name “CLARITY” concluded that no evidence of benefit, based on disease severity score, was found for treatment with angiotensin receptor blockers in patients with mild disease, not requiring oxygen, administered orally 40 mg/day of telmisartan [245]. A seamless phase I and II study, infusing angiotensin (1–7) intravenously in COVID-19 patients admitted to the ICU (Intensive Care Unit) with severe pneumonia at 10 mcg/Kg daily is safe. In the Phase II intention-to-treat analysis, there was no significant difference in oxygen-free days (OFD) between groups. However, phase II was terminated prematurely due to low recruitment rates and funding shortages, limiting the interpretation of these data [246]. Further, studies need to be performed in order to properly assess the therapeutic potential of sartan derivatives.

3.17. Rheumatoid Arthritis

Rheumatoid arthritis (RA) and osteoarthritis (OA) represent the two primary types of inflammatory arthritis. Although RA and OA have distinct mechanisms of development, they share certain similarities. In both cases, ongoing inflammation causes gradual damage to the joints. The renin–angiotensin system (RAS) plays a role in the development of both RA and OA [247].
RA is a significant condition that impacts joints by increasing inflammation and leading to periarticular osteopenia. Due to the numerous side effects associated with current RA treatments, finding alternative therapies has become a crucial area of research. A local functional RAAS has been identified in various organs and tissues, such as chondrocytes, synovial fluid, and synovial tissue. ACE and renin concentrations were also higher at the synovial fluid in RA patients. The generated Ang II increases pro-inflammatory cytokines like IL-1, IL-6, and TNF-α, which may play a role in the development of RA. Both experimental and clinical research indicate that RAS inhibitors—especially ARBs, as well as ACE inhibitors and renin inhibitors—play a role in RA by primarily targeting inflammation and oxidative stress [247].

3.18. Osteoarthritis

Osteoarthritis (OA) is a painful joint condition characterized by the gradual breakdown of cartilage, resulting in discomfort and reduced movement. Existing diagnostic techniques and the absence of treatments that alter disease progression emphasize the urgent need for new management approaches. Recent studies indicate that the RAAS, especially the effects of Ang II on AT1 and AT2 receptors in synovial tissue, could be crucial in the development of osteoarthritis and rheumatoid arthritis. Excessive activation of AT1R is associated with diseases like hypertension and cardiovascular fibrosis, which have similarities to osteoarthritis. In joint tissues—such as cartilage and synovium—AT1R stimulation by Ang II or inflammatory cytokines like IL-1β triggers the release of pro-inflammatory substances and matrix metalloproteinases (MMPs), speeding up cartilage degradation and worsening joint injury. RAS modulators, including ARBs and ACEIs, are being investigated as possible treatments for osteoarthritis. Kaur et al. [248] found that inhibition of the AT1 receptor shows promise in reducing IL-1β-driven inflammation, extracellular matrix (ECM) breakdown, and chondrocyte death in osteoarthritis, while also promoting ECM production, autophagy, and protection of cartilage cells. These effects are regulated by key transcription factors such as STAT3, NF-κB, MAPK, vascular endothelial growth factor (VEGF), and Caspase 3. The results reveal not only the cartilage-protecting benefits of these drugs but also clarify how they reduce inflammation and support chondrocyte survival, providing valuable understanding for potential treatment options [248]. No clinical trials have been performed with regard to treating OA with sartans. One clinical study assessing the antihypertensive drug-associated adverse events in osteoarthritis in patients with OA and hypertension found that valsartan had strong osteoarthritis adverse reaction signals among the three ARBs, namely, irbesartan, cloxartan, and valsartan [249].

3.19. Opioid Addiction

Drug use is a continually rising problem in developed countries, with a representative example being the US where more than 23 million adults struggle with addiction [250]. In 2017, the US Department of Health and Human Services declared the opioid problem as an epidemic, which accounted for more than 42,000 deaths in 2016 [251]. Opiates are much more addictive than other kinds of substances, which poses an even bigger threat in society. In an attempt to tackle opiate addiction, based on the principles of drug repositioning, Ridgway et al. [252] utilized computational chemistry tools to unravel crossover binding patterns of diverse ligands to angiotensin, alpha-adrenergic, and opioid receptors. Their work was based on recent bioassay studies which were in agreement with the high (computationally predicted) binding affinities of angiotensin receptor blockers (ARBs) at α-adrenergic receptors (αARs) in isolated smooth muscle. Via the use of docking and molecular dynamics (MD) simulations, they explored the affinities and stabilities of selected non-peptide ligands (of which and sartans) on several G protein-coupled receptors GPCRs, including α1AR, α2AR, and µ-(µOR) and ժ-opioid receptors (ժOR). This procedure showed that these ligands preferentially bind to the active site on the cell surface of all three GPCR receptors, with a consistent order of ligand preference, while the blockade they present to αARs and µORs has been confirmed by bioassay studies as well. Moreover, in their results, ARBs which exhibit higher affinities for AT1 receptor also demonstrate higher affinities for µORs and ժORs than opiate ligands, such as fentanyl and naltrexone, showcasing the high number of possibilities these molecules can have in combating opiate addiction. Interestingly, ARBs had, also, a higher affinity for αARs than either alpha agonists (epinephrine and phenylephrine) or inhibitors (prazosin and doxazosin). Finally, tested compounds sartans and bisartans appeared to interfere with the desensitization and/or re-sensitization (tolerance) mechanisms of αARs and µORs, thus proposing their potential role in the treatment of methamphetamine and opioid addiction (OPA) [252]. There are no ongoing clinical trials to study the utilization of ARBs in opioid addiction.
A summary of the diseases, the mechanistic rationale, and the involvement of the RAAS in their development is provided in Table 2.

4. Novel Synthetic AT1 Antagonists and Dual Inhibitors

As shown in Table 3, non-peptide molecules with a smaller scaffold than common drugs were synthesized and studied in our laboratories. Thus, (5S)-1-benzylo-5-(1H-imidazol-1ylo-methylo-)-2-pyrrolidinone (MM1) was created, matching a simpler synthetic root compared to sartans and a significant antihypertensive activity (71% compared to losartan defined as 100% losartan) when injected to anesthetized rabbits made hypertensive by Ang II infusion [284]. Since these molecules possessed strong inhibitory activity against the AT1 receptor, new paths in drug discovery were opened. MMK2 and MMK3 were also synthesized, later possessing 80% and 48% antihypertensive activity relative to losartan at the same experimental conditions. However, the in vitro experiments, using membranes with AT1 receptors and cell cultures, showed that compounds MM1, MMK2, and MMK3 exhibited negligible activity compared to the reference drug losartan (IC50 ≈ 10−9 M) for the AT1 receptor [285].
Continuing our work, our laboratory designed, synthesized, and evaluated derivatives of losartan in vitro and in vivo, as can be seen by the second group shown in Table 3. Derivative V-8 exhibited an angiotensin II antagonistic effect in vivo (rabbits) that increased with dosage at 2 and 3.5 µmol, similar to the effects seen with losartan. In vitro binding experiments demonstrated that V-8 exhibited strong affinity for the AT1 receptor, specifically within the nanomolar range, similar to losartan (IC50 of V-8: 53.8 ± 6.4 nM; IC50 of losartan: 16.4 ± 1.6 nM) while it did not bind on the AT2 receptor [286,287]. N-substituted 5-butylimidazole derivatives were also synthesized, from which the compound 5-butyl-1-[[20-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl] imidazole-2-carboxylic acid (30) exhibited higher binding affinity (−log IC50 = 8.46) for the AT1 receptor compared to losartan (−log IC50 = 8.25) [288]. Moreover, N,N’-symmetrically bis-substituted butylimidazole analogs have been synthesized and studied. From these analogs, compounds 11 (also named BV6 and BisA in other citations), 12a, 12b, and 14 (also named BisB) showcased higher antagonistic activity (potency) when compared to losartan (11; −logIC50 = 9.46, 12a; −logIC50 = 9.04, 12b; −logIC50 = 8.54, 14; −logIC50 = 8.37 and losartan; −logIC50 = 8.25). Specifically, compound 11 was designed to have most of the pharmacological segments of losartan and an additional biphenyltetrazole moiety, resulting in increased lipophilicity. These compounds are bis-alkylated imidazole sartan derivatives, called “bisartans”, designed to fill a lipophilic cavity that sartans do not accommodate [222,288,289,290,291,292].
Since many diseases are actually multifactorial, we decided to expand our research of AT1 inhibition to other drug targets as well. As such dual inhibitors were designed, synthesized, and studied in silico, in vitro, and in vivo. Characteristic examples are quercetin–losartan hybrids for the treatment of glioblastoma multiforme (GBM). In GBM cells, we showed that this (Q-L) hybrid retains the binding potential of losartan to the AT1R (Q-L IC50; 140 ± 10 nM, losartan IC50; 10.3 ± 1.1 nM) through competition-binding experiments and simultaneously exhibits ROS inhibition and antioxidant capacity similar to native quercetin. Moreover, it appeared that the hybrid can modify the cell-cycle distribution in GBM cells, causing cell-cycle arrest and triggering cytotoxic effects and inhibits cancer cell proliferation and angiogenesis in primary GBM cultures [293]. Another example is a DHA–losartan hybrid used as a potent inhibitor of multiple pathway-induced platelet aggregation. The hybrid demonstrated a broad-spectrum antiplatelet effect by inhibiting platelet aggregation via multiple activation pathways, including P2Y12, PAR-1 (Protease-Activated Receptor-1), PAF (Platelet-Activating Factor), COX-1 (cyclooxygenase-1), and collagen receptors (collagen; losartan IC50; 112.9 μΜ, DHA IC50; 185.6 μΜ and DHA–losartan hybrid IC50; 249.1 μΜ) [294]. The synthetic routes for AT1 antagonists and more specifically sartan derivatives are established and reviewed by our laboratories and specifically Georgiou et al. [295].
We have also scanned compound databases like ChEMBL15 and discovered a lot of molecules that could possibly be used for AT1 inhibition. All analogs bound to the AT1 receptor in a dose-dependent manner, showing significant binding affinities (−log IC50). Specifically, the −log IC50 values for compounds 1, 2, 3, and 4 (Table 3) were 5.66 ± 0.14, 5.68 ± 0.26, 5.59 ± 0.33, and 6.70 ± 0.19, respectively. Notably, compound 4 exhibited a binding affinity to the AT1 receptor that was approximately 10 times higher than the other compounds and closer to that of losartan, which had a value of 8.49 ± 0.18.73 [296]. All the aforementioned molecules are shown in Table 3.
Based on the bibliographic search we conducted, there are no instances of synthesized small molecules with a small non-peptide scaffold to be comparable to compounds MM1, MMK2, and MMK3 as showcased in Table 3. Nevertheless, different scientific groups have given the name “small non-peptide” to their sartan derivatives, and we refer to some of them in Table 4. Below, we showcase representative examples of different sartan derivatives.
KRH-594 (Table 4), synthesized by Kissei Pharmaceutical Co., Ltd. (Hotaka, Japan) [297,298], is another instance of a non-peptide molecule exhibiting potent pharmacodynamic properties for the inhibition of the AT1 receptor. In particular, the compound potently displaced specific binding of [125I]-Ang II at the AT1 receptor with a Ki = 0.39 ± 0.08 nM (n = 4). When compared to losartan and its metabolite EXP3174 with Ki values of 14 ± 3.0 nM (n = 4) and 0.79 ± 0.18 nM (n = 3), respectively, its potency becomes evident ( ~ 36-fold more potent as an AT1 antagonist than losartan and twofold more potent than EXP3174). On the other hand, it did not show the same effects for the AT2 receptor in bovine cerebellar membranes (Ki > 10 μM) (>25,000-fold higher affinity for AT1). The strong specificity of KRH-594 for the AT1 receptor subtype was further confirmed by its lack of binding affinity to various other receptors and enzymes at a concentration of 10 μM. All these findings demonstrate that KRH-594 is a potent and highly selective AT1 receptor antagonist [299]. Interestingly, while this compound has a very promising pharmacologic profile according to preclinical studies, no further attempt was made to evaluate this compound in clinical trials to this date.
Another compound worth mentioning is KT3–671 (now also known as KD3-671) (Table 4) synthesized by Mochizuki et al. [300], as a non-peptide molecule for the antagonism of the AT1 receptor. KT3–671 displaced specific binding of [125I]Sar1 Ile8-Ang II to AT1 receptor with a Ki value of 0.71 ± 0.14 nM in rat liver membranes, but had no affinity for AT2 receptor in bovine cerebellar membranes (Ki > 10 μM). When compared with losartan (DuP 753) and EXP3174, which displaced the specific binding of the radioligand to AT1 receptor, with Ki values of 5.02 ± 1.63 and 0.32 ± 0.06 nM, respectively, it shows a strong affinity for this receptor. This compound went also to clinical trials where in a phase II randomized double-blind study of patients with mild to moderate essential hypertension, KT3-671 (20–80 mg) demonstrated a shallow dose–response relationship for reductions in sitting trough blood pressure (BP). Significant effects were observed only for sitting office diastolic BP compared with placebo, while reductions in ambulatory blood pressure (ABP) were more pronounced than those in office trough BP [300]. Another study aimed to evaluate the antihypertensive efficacy of once-daily KT3-671 doses of up to 160 mg (40, 80, and 160 mg) compared with placebo in patients with mild to moderate uncomplicated essential hypertension. Only the 40 mg dose showed a statistically significant difference from the placebo group for the primary efficacy measure. The researchers concluded that, at suitable doses, KT3-671 could serve as an effective once-daily antihypertensive agent. It was well tolerated across all three tested doses, consistent with the characteristic of AT1 receptor blockers that adverse effects are not dose-dependent [301].
Many derivatives of losartan have been synthesized throughout the years, with the intention of improving its affinity to the AT1 receptor and the lives of patients. Han et al. [302] developed novel angiotensin II receptor type 1 (AT1) blockers bearing 6-substituted carbamoyl benzimidazoles with a chiral center and tried to understand its pharmacodynamic properties. Blood-pressure screening in spontaneously hypertensive rats revealed that the most pronounced activity, compared to losartan (IC50 = 28.6 ± 2.0 nM), was observed with compound 8R (IC50 = 1.1 ± 0.5 nM). Compound 8R (Table 4) was identified as a promising candidate due to its strong antihypertensive efficacy and relatively low toxicity, as evidenced by plasma analyses, toxicology studies, and chronic oral testing. Docking studies further revealed that 8R forms multiple robust interactions with the active sites of the theoretical AT1 receptor model [302].
Zhu et al. [303] designed, synthesized and evaluated in vitro and in vivo, 6-substituted benzimidazole with 1, 4-disubsituted or 1, 5-disubsituted indole derivatives as novel angiotensin II receptor antagonists. Biological evaluation in spontaneously hypertensive rats demonstrated that 2-[4-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazole-1-yl]methyl]-1H-indol-1-yl]benzoic acid; compound 1c (IC50 = 0.36 ± 0.18 nM, Ki = 0.23 ± 0.17 nM) (Table 4) produced a significant, dose-dependent reduction in mean blood pressure (MBP). Oral administration resulted in maximal decreases of 53 mmHg at 5 mg/kg and 64 mmHg at 10 mg/kg, with the antihypertensive effect persisting for over 24 h—surpassing the efficacy of both losartan (IC50 = 20.09 ± 0.11 nM, Ki = 13.06 ± 0.07 nM) and telmisartan (IC50 = 3.80 ± 0.22 nM, Ki = 2.75 ± 0.17 nM). Acute toxicity studies further indicated that 1c exhibited low toxicity, with no notable weight changes or adverse reactions observed, making it an effective and durable anti-hypertension drug candidate, deserving further investigation for therapeutic application [303].
5-oxo-1,2,4-oxadiazole derivatives with 1, 4-disubsituted or 1, 5-disubsituted indole group were, also, designed, synthesized, and pharmacologically evaluated by Zhu. et al. [304]. These derivatives exhibited strong affinities for the AT1 receptor, comparable to losartan (IC50 = 10.51 ± 2.19 nM, Ki = 7.61 ± 1.59 nM), but they were not as potent as irbesartan (IC50 = 1.30 ± 0.06 nM, Ki = 0.94 ± 0.04 nM). The methyl ester containing a 1,4-disubstituted indole group, compound 1 (IC50 = 5.01 ± 1.67 nM, Ki = 3.63 ± 1.21 nM) (Table 4), demonstrated potent antihypertensive activity in spontaneously hypertensive rats (SHRs). Following oral administration at 10 mg/kg, it reduced mean blood pressure (MBP) by 30 mmHg, surpassing the effect of irbesartan, with the antihypertensive response persisting for over 24 h. Compound 1 had low acute toxicity; however, hyperthyroidism appeared 6 h later after administration in other groups, and some mice died. There were no significant changes in the weight of the surviving mice after 2 weeks of observation and no obvious untoward reactions appeared [304].
A series of novel oxadiazole derivatives were designed, synthesized, and evaluated for their pharmacological effects by Qu et al. [305]. These compounds exhibited strong affinity for the AT1 receptor and produced significant blood pressure reductions in spontaneously hypertensive rats at nanomolar concentrations. Notably, compounds IV1 (Table 4) with an IC50 value of 7.7 ± 1.2 nM and Ki = 5.5 ± 0.6 nM and IV2 (Table 4) with IC50 = 8.0 ± 0.5 nM and Ki = 5.8 ± 0.4 nM proved especially effective, showing equal or greater potency than losartan (IC50 = 14.6 ± 1.6 nM, Ki = 10.5 ± 1.2 nM), highlighting their potential as candidates for antihypertensive drug development [305].
Tang et al. [306] designed and synthesized (2-(4-((2-amyl-5-nitro-1H-benzo[d]-imidazol-1-yl) methyl)-1H-indol-1-yl) tetrazole); compound 1a (Table 4). The compound 1a had a higher affinity to bind with AT1 receptor (1a: IC 50 = 4.05 ± 2.11 nM, Ki = 2.93 ± 1.53 nM) compared to losartan (IC50 = 12.23 ± 3.42 nM, Ki = 8.86 ± 2.49 nM). It was prepared and orally administered to spontaneous hypertensive rats to study the antihypertensive effects. The maximum reduction in blood pressure reached 50 mmHg after dosing compound 1a for 5 h (dose of 10 mg/kg). However, at the same dose, losartan reached the maximum hypotensive value at 45 mmHg in 3 h and antihypertensive activity in 12 h. Compound 1a demonstrated greater efficacy in reducing blood pressure at the same dose, with improved stability and a more sustained effect [306].
Zhu et al. [307] designed, synthesized, and evaluated 5-nitro benzimidazole in vitro and in vivo with 1,4-disubsituted or 1,5-disubsituted indole derivatives as novel angiotensin II receptor antagonists. Radioligand-binding assays showed that 2-(4-((2-butyl-5-nitro-1H-benzo[d]imidazol-1-yl)methyl)-1H-indol-1-yl)benzoic acid, compound 3 (Table 4), displayed a high affinity for the angiotensin II type 1 receptor with IC50 value of 1.03 ± 0.26 nM and Ki value of 0.97 ± 0.43 nM (higher compared to losartan; IC50 = 3.54 ± 0.34 nM, Ki = 2.53 ± 1.12). The biological evaluation on spontaneously hypertensive rats and renal hypertensive rats showed that 3 could cause a significant decrease on MBP in a dose-dependent manner, whose maximal response lowered 30 mmHg of MBP at 5 mg/kg and 41 mmHg of MBP at 10 mg/kg after oral administration, and the significant antihypertensive effect lasted beyond 24 h, which is better than losartan. Taken together, 3 could be considered as an effective and durable anti-hypertension drug candidate. These encouraging results deserve further investigation towards its use for therapeutic benefit [307].
Table 3. Presentation of the key compounds with significant biological activity that were designed, synthesized, and studied computationally and pharmacologically by our research team and collaborators over the years, grouped according to the methodology used to design them. Four major groups are outlined. Group A, small non-peptide molecules; Group B, sartan derivatives; Group C, hybrid molecules; and Group D, databases.
Table 3. Presentation of the key compounds with significant biological activity that were designed, synthesized, and studied computationally and pharmacologically by our research team and collaborators over the years, grouped according to the methodology used to design them. Four major groups are outlined. Group A, small non-peptide molecules; Group B, sartan derivatives; Group C, hybrid molecules; and Group D, databases.
Structures of Bioactive CompoundsBiological Evaluation
Group A: small non-peptide molecules
Ijms 26 08819 i001Significant antihypertensive activity (MM1: 71% and MMK2: 80% when compared to losartan defined as 100% losartan) when injected to anesthetized rabbits made hypertensive by Ang II infusion. In vitro experiments showed that compounds MM1 and MMK2 exhibited negligible activity compared to the reference drug losartan [284,285].
Ijms 26 08819 i002Antihypertensive activity (MMK3: 48% when compared to losartan defined as 100% losartan) when injected to anesthetized rabbits made hypertensive by Ang II infusion. In vitro experiments showed that compound MMK3 exhibited negligible activity compared to the reference drug losartan [285].
Group B: sartan derivatives
Ijms 26 08819 i003In vitro binding studies; higher affinity of V8 when compared to losartan for the AT1 receptor (V8: IC50 = 53.8 ± 6.4 nM and losartan; IC50 = 16.4 ± 1.6 nM). V8 is a selective AT1 antagonist [286,287].
Ijms 26 08819 i004Higher binding affinity of compound 30 compared to losartan (30: −logIC50 = 8.46; and losartan: −logIC50 = 8.25). Importance of carboxy group at the C-2 position [288].
Ijms 26 08819 i005Compounds 11 (also named BV6 or BisA), 12a and 12b showcase higher antagonistic activity (potency) when compared to losartan (11: −logIC50 = 9.46; 12a: −logIC50 = 9.04; 12b: −logIC50 = 8.54; and losartan: −logIC50 = 8.25). Compound’s 11 elevated docking score for the AT1 receptor is due to a greater number of hydrophobic interactions compared to losartan [222,288,289,290,291,292].
Ijms 26 08819 i006Compound 14 (also named BisB) showcases higher antagonistic activity (potency) when compared to losartan (14: −logIC50 = 8.37; and losartan: −logIC50 = 8.25) [222,288,289,290,291,292].
Group C: hybrid molecules
Ijms 26 08819 i007The quercetin–losartan (Q-L) hybrid retains the binding potential of losartan to the AT1R (Q-L IC50: 140 ± 10 nM; losartan IC50: 10.3 ± 1.1 nM), exhibits ROS inhibition and antioxidant capacity similar to native quercetin, modifies the cell-cycle distribution in GBM cells, and inhibits cancer cell proliferation and angiogenesis in primary GBM cultures [293].
Ijms 26 08819 i008DHA–losartan; potent inhibitor of multiple pathway-induced platelet aggregation, like P2Y12, PAR-1 (Protease-Activated Receptor-1), PAF (Platelet-Activating Factor), COX-1 (cyclooxygenase-1), and collagen receptors (collagen; losartan IC50: 112.9 μΜ; DHA IC50: 185.6 μΜ; and DHA–losartan hybrid IC50: 249.1 μΜ) [294].
Group D: databases
Ijms 26 08819 i009Compound 1 shows good binding affinity for the AT1 receptor but not better than losartan (1: −logIC50 = 5.66 ± 0.14; and losartan: −logIC50 = 8.49 ± 0.18) [296].
Ijms 26 08819 i010Compound 2 shows good binding affinity for the AT1 receptor but no better than losartan (2: −logIC50 = 5.68 ± 0.26; and losartan: −logIC50 = 8.49 ± 0.18) [296].
Ijms 26 08819 i011Compound 3 shows the worst binding affinity for the AT1 receptor compared to 1 and 2 and no better than losartan (3: −logIC50 = 5.59 ± 0.33; and losartan: −logIC50 = 8.49 ± 0.18) [296].
Ijms 26 08819 i012Compound 4 has 10-fold higher binding affinity for the AT1 receptor compared to 1, 2, and 3 but is not better than losartan (4: −logIC50 = 6.70 ± 0.19; and losartan: −logIC50 = 8.49 ± 0.18) [296].
Table 4. Presentation of selected compounds with significant biological activity that were designed, synthesized, and studied pharmacologically by different research groups over the years, for comparative purposes.
Table 4. Presentation of selected compounds with significant biological activity that were designed, synthesized, and studied pharmacologically by different research groups over the years, for comparative purposes.
Structures of Bioactive CompoundsBiological Evaluation
Group A; Sartan Derivatives
Ijms 26 08819 i013In vitro binding studies; higher affinity of KRH-594 when compared to losartan and its active metabolite EXP3174 for the AT1 receptor [KRH-594: Ki = 0.39 ± 0.08 nM (n = 4), losartan; Ki = 14 ± 3.0 nM (n = 4) and Ki = 0.79 ± 0.18 nM (n = 3)] [299].
Ijms 26 08819 i014In vitro binding studies; higher affinity of KT3–671 when compared to losartan and its active metabolite EXP3174 for the AT1 receptor [KT3–671: Ki = 0.71 ± 0.14 nM; losartan (DuP 753): Ki = 5.02 ± 1.63 nM (n = 4); and EXP3174: Ki = 0.32 ± 0.06] [301]. Strong affinity for this receptor in rat liver membranes.
Ijms 26 08819 i015In vitro binding studies; higher activity of 8R when compared to losartan for the AT1 receptor (8R: IC50 = 1.1 ± 0.5 nM and losartan: IC50 = 28.6 ± 2.0 nM). Promising candidate due to its strong antihypertensive efficacy and relatively low toxicity, as evidenced by plasma analyses, toxicology studies, and chronic oral testing [302].
Ijms 26 08819 i016Oral administration of compound 1c (IC50 = 0.36 ± 0.18 nM, Ki = 0.23 ± 0.17 nM) resulted in maximal decreases of 53 mmHg at 5 mg/kg and 64 mmHg at 10 mg/kg, with the antihypertensive effect persisting for over 24 h—surpassing the efficacy of both losartan (IC50 = 20.09 ± 0.11 nM, Ki = 13.06 ± 0.07 nM) and telmisartan (IC50 = 3.80 ± 0.22 nM, Ki = 2.75 ± 0.17 nM) [303].
Ijms 26 08819 i017Compound 1 (IC50 = 5.01 ± 1.67 nM, Ki = 3.63 ± 1.21 nM) shows good binding affinity for the AT1 receptor, comparable to losartan (IC50 = 10.51 ± 2.19 nM, Ki = 7.61 ± 1.59 nM), but weaker than irbesartan (IC50 = 1.30 ± 0.06 nM, Ki = 0.94 ± 0.04 nM). It reduced MBP by 30 mmHg, surpassing the effect of irbesartan, and had low acute toxicity [304].
Ijms 26 08819 i018Compound IV1 (IC50 = 7.7 ± 1.2 nM, Ki = 5.5 ± 0.6 nM) proved especially effective, showing greater potency than losartan (IC50 = 14.6 ± 1.6 nM, Ki = 10.5 ± 1.2 nM), highlighting its potential as a drug candidate [305].
Ijms 26 08819 i019Compound IV2 with IC50 = 8.0 ± 0.5 nM and Ki = 5.8 ± 0.4 nM showed greater potency than losartan (IC50 = 14.6 ± 1.6 nM, Ki = 10.5 ± 1.2 nM), highlighting its potential as a candidate for antihypertensive drug development [305].
Ijms 26 08819 i020Compound 1a has a higher affinity to bind with AT1 receptor (1a: IC 50 = 4.05 ± 2.11 nM, Ki = 2.93 ± 1.53 nM) compared to losartan: (IC50 = 12.23 ± 3.42 nM, Ki = 8.86 ± 2.49 nM) [306].
Ijms 26 08819 i021Compound 3, displayed a high affinity for the angiotensin II type 1 receptor with IC50 value of 1.03 ± 0.26 nM and Ki value of 0.97 ± 0.43 nM (higher compared to losartan; IC50 = 3.54 ± 0.34 nM, Ki = 2.53 ± 1.12) [307].
The compounds we have synthesized along with our collaborators have been organized into four separate groups and can be seen in Figure 2.

5. Bisartans: Second-Generation Non-Peptide Mimetics of Ang II as Pan-Antiviral Drugs

Second-generation ARB bisartans are discovered in our laboratories [222,288,289,290,291,292], in which both imidazole nitrogens are substituted with biphenyltetrazole and exhibit remarkable affinity and strong binding to the catalytic sites of viruses SARS-CoV-2, influenza, and Respiratory Syncytial Viruses, rendering them potential pan-antiviral drugs [308]. This property may derive from the dual interaction of both warhead negative tetrazoles with positive arginines which trigger infections [222,309]. For an analytical presentation of the interactions and the anti-viral effects exerted by our bisartans compared to other drug entities, you can refer to the article by Ridgway et al. [308]. Pioneer research earlier on the design and synthesis of losartan analogs has led to the discovery of a new class of ARBs where the imidazole substituents, i.e., the butyl and hydroxyl methylene groups at positions 2 and 4, respectively, are at reversed positions compared to losartan [286,287,288]. These analogs were the basis for further developing bisalkylated derivatives which symmetrically bear two biphenyl tetrazole groups on the two imidazole nitrogens, called bisartans, with notable properties relevant to hypertension and coronavirus 2019 therapies [222,288,289,290,291,292].
The use of benzimidazole as a scaffold instead of imidazole and bis biphenyl tetrazole alkylation resulted in the development of new bisartans, which exhibited the unique binding affinities due to tetrazole and increased aromaticity [310]. Interaction of aromatic phenyl groups with arginines, as between ARBs and AT1R R167, has been previously reported as a dominant binding factor due to the π-π electron interactions [311,312,313,314]. Arginine is a key amino acid in disease, and arginine blockers, like ARBs or bisartans containing warhead anionic tetrazoles, are emerging as promising pharmaceutics to battle arginine-based viruses and other diseases. The unique and fascinating properties of tetrazole have recently received significant attention in medicinal chemistry for innovative therapies [211,315].

6. Conclusions

The renin–angiotensin–aldosterone system (RAAS) plays a crucial role in regulating vascular tone and maintaining fluid balance. In the classical pathway, prorenin is converted into renin in the kidneys. Afterwards, renin converts angiotensinogen into angiotensin I (Ang I) which is metabolized to angiotensin II (Ang II) and binds to angiotensin II type 1 (AT1) receptors, resulting in elevated blood pressure through vasoconstriction, sympathetic activation, and enhanced sodium retention. Thus, AT1 antagonists are used in the treatment for hypertension and cardiovascular diseases like heart failure, chronic kidney disease, and acute coronary syndrome. Due to the fact that this system is a highly complex hormonal cascade that spans multiple organs and cell types, it becomes evident that it plays an important role in the occurrence of multiple diseases when it malfunctions. Drug repurposing is a convenient way of utilizing existing drugs, such as angiotensin II receptor blockers (ARBs), towards the therapy of different diseases. In this review, we have outlined the importance of drug repurposing (repositioning) for AT1 antagonists and in some cases ACE inhibitors (ACEIs). Examples are given for neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, anxiety, certain types of cancer like glioma, etc. These studies are very promising and, in combination with rational drug design along with the creation of hybrid molecules for the selective inhibition of multiple targets, many new possibilities arise towards the resolution of various pathological conditions. For example, the design of a compound which processes the inhibitory activity of losartan (AT1 inhibitor) and Lanabecestat (a potent BACE1 inhibitor) could open new paths in the treatment of Alzheimer’s disease. Finally, we discuss our own research on novel AT1 antagonists. These molecules range from small non-peptide compounds to sartan derivatives and hybrid molecules. It becomes evident that the possibilities for ARB utilization towards the synthesis or improvement of already existing compounds are many and our research should head towards this goal.

Author Contributions

F.P.C. is the main author of this review and the creator of the tables and figures. K.M. has contributed with the parts on the role of the renin–angiotensin–aldosterone system (RAAS) and heart failure, chronic kidney disease and acute coronary syndrome. She has, also, contributed noteworthy corrections to the manuscript so as to ensure a better structure. Professor J.M.M. has provided the first paragraph in Section 3.1 entitled “Hypertension”, a part in Section 3.8 entitled “Cancer Glioma”, a part in Section 3.9 entitled “Pathogenic Inflammation”, and Section 5, entitled “Bisartans: Second-Generation Non-Peptide Mimetics of Ang II as Pan-Antiviral Drugs”. He has also contributed to the overall formatting of the text. Professor T.M. is responsible for the thematic development and overall supervision of the quality of the final text, providing corrections where required. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

J.M.M. is an employee of NewDrug, P.C. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
RAASRenin–Angiotensin–Aldosterone system (RAAS)
Ang IAngiotensin I
Ang IIAngiotensin II
ACEAngiotensin-converting enzyme
AT1RAngiotensin II Type 1 receptor
AT2RAngiotensin II Type 2 receptor
MTDLsMulti-target Directed Ligands
HTHypertension
HFHeart Failure
CKDChronic Kidney disease
ACSAcute Coronary Syndrome
ADAlzheimer’s disease
PDParkinson’s disease
RARheumatoid Arthritis
OAOsteoarthritis
DNDiabetic Nephropathy
DPNDiabetic Peripheral Neuropathy
SARS-CoV-2Severe Acute Respiratory Syndrome Coronavirus 2
CSCandidosis
FSFibrosis
TFSScTissue Fibrosis in Systemic Sclerosis
RPRaynaud’s phenomenon
GCGlioma Cancer
EAEAuto-immune encephalomyelitis
MSMarfan Syndrome
MBPMyelin Basic Protein
IBDsInflammatory Bowel diseases
TH17T helper 17
AktProtein kinase B
ICUIntensive Care Unit
ATAnxiety
PIPathogenic Inflammation
YUYet Unknown diseases
UKUnited Kingdom
PDE5Phosphodiesterase-5
cGMPCyclic Guanosine Monophosphate
NONitric Oxide
CADCoronary Artery disease
CRSCharge Relay System
ARBsAngiotensin II receptor blockers
CCBsCalcium channel blockers
ARNIsAngiotensin receptor neprilysin inhibitors
ESCEuropean Society of Cardiology
HFrEFHeart Failure with Reduced Ejection Fraction
HFmrEFHeart Failure with Mid-Range Ejection Fraction
KDIGOKidney Disease: Improving Kidney Outcomes
APPAmyloid precursor protein
Amyloid-beta
BACE1Beta-site amyloid precursor protein-cleaving enzyme 1 inhibitors
CSFCerebrospinal fluid
AT4Angiotensin IV receptor
ACEIsAngiotensin-converting enzyme inhibitors
AngAngiotensin
DADopamine
ROSReactive Oxygen Species
STAIState-Trait Anxiety Inventory
BBBBlood–Brain Barrier
FDAFood and Drug Administration
U87Uppsala 87 Malignant Glioma
PCRPolymerase Chain Reaction
TNF-αTumor necrosis factor alpha
IL-6Interleukin-6
NLRP3NOD-like receptor family pyrin domain containing 3
proIL-1βpro-interleukin-1β
NF-κBNuclear factor kappa light chain enhancer of activated B cells
ERK1/2Extracellular signal-regulated kinase 1 and 2
JNK1/2c-Jun N-terminal kinase 1 and 2. to PKR, NEK7, and ASC.
AP-1Activator Protein-1
LVEFLeft Ventricular Ejection Fraction
PKRProtein kinase R
NEK7NIMA-related kinase 7
ASCApoptosis-associated speck-like protein containing a CARD
T2DMType 2 diabetes mellitus
FBN1Fibrillin-1
Ang (1–7)Angiotensin (1–7)
IL-1Interleukin-1
MMPsMatrix metalloproteinases
ECMExtracellular matrix
TGF-βTransforming Growth Factor-β
CVDCardiovascular disease
NADPHNicotinamide Adenine Dinucleotide Phosphate
MASMAS proto-oncogene
IRIIschemia–Reperfusion Injury
CRHCorticotropin-releasing hormone
AVPArginine Vasopressin
STAT3Signal transducer and activator of transcription 3
MAPKMitogen-activated protein kinase
CDCrohn’s disease
UCUlcerative colitis
VEGFVascular endothelial growth factor
Caspase-3Cysteine-aspartic acid protease 3
IC50Half-maximal inhibitory concentration
GBMGlioblastoma multiforme
PBMCPeripheral Blood Mononuclear Cells
MHC IIMajor Histocompatibility Complex Class II molecule
SmadSuppressor of Mothers against Decapentaplegic
IRE1α-XBP1Inositol-Requiring Enzyme 1 alpha-X-Box Binding Protein 1
AKIAcute Kidney Injury
DHADocosahexaenoic acid
P2Y12Purinergic Receptor P2Y, G-protein coupled 12
PAR-1Protease-Activated Receptor-1
PAFPlatelet-Activating Factor
COX-1Cyclooxygenase-1
MDMolecular Dynamics
GPCRsG protein-coupled receptors
α1ARα1-adrenergic receptor
α2ARA2-adrenergic receptor
µ-(µOR)μ-opioid receptor
ժORδ-opioid receptor

References

  1. Pan, X.; Lin, X.; Cao, D.; Zeng, X.; Yu, P.S.; He, L.; Nussinov, R.; Cheng, F. Deep Learning for Drug Repurposing: Methods, Databases, and Applications. WIREs Comput. Mol. Sci. 2022, 12, e1597. [Google Scholar] [CrossRef]
  2. Parvathaneni, V.; Kulkarni, N.S.; Muth, A.; Gupta, V. Drug Repurposing: A Promising Tool to Accelerate the Drug Discovery Process. Drug Discov. Today 2019, 24, 2076–2085. [Google Scholar] [CrossRef]
  3. Singh, T.U.; Parida, S.; Lingaraju, M.C.; Kesavan, M.; Kumar, D.; Singh, R.K. Drug Repurposing Approach to Fight COVID-19. Pharmacol. Rep. 2020, 72, 1479–1508. [Google Scholar] [CrossRef]
  4. Kulkarni, V.S.; Alagarsamy, V.; Solomon, V.R.; Jose, P.A.; Murugesan, S. Drug Repurposing: An Effective Tool in Modern Drug Discovery. Russ. J. Bioorg. Chem. 2023, 49, 157–166. [Google Scholar] [CrossRef]
  5. Masoudi-Sobhanzadeh, Y.; Omidi, Y.; Amanlou, M.; Masoudi-Nejad, A. Drug Databases and Their Contributions to Drug Repurposing. Genomics 2020, 112, 1087–1095. [Google Scholar] [CrossRef]
  6. Dotolo, S.; Marabotti, A.; Facchiano, A.; Tagliaferri, R. A Review on Drug Repurposing Applicable to COVID-19. Brief. Bioinform. 2021, 22, 726–741. [Google Scholar] [CrossRef]
  7. Parisi, D.; Adasme, M.F.; Sveshnikova, A.; Bolz, S.N.; Moreau, Y.; Schroeder, M. Drug Repositioning or Target Repositioning: A Structural Perspective of Drug-Target-Indication Relationship for Available Repurposed Drugs. Comput. Struct. Biotechnol. J. 2020, 18, 1043–1055. [Google Scholar] [CrossRef]
  8. Mishra, A.S.; Vasanthan, M.; Malliappan, S.P. Drug Repurposing: A Leading Strategy for New Threats and Targets. ACS Pharmacol. Transl. Sci. 2024, 7, 915–932. [Google Scholar] [CrossRef]
  9. Maggioni, A.P. Efficacy of Angiotensin Receptor Blockers in Cardiovascular Disease. Cardiovasc. Drugs Ther. 2006, 20, 295–308. [Google Scholar] [CrossRef]
  10. Maggioni, A.P.; Latini, R. The Angiotensin-Receptor Blockers: From Antihypertensives to Cardiovascular All-Round Medications in 10 Years? Blood Press. 2002, 11, 328–338. [Google Scholar] [CrossRef]
  11. Qaradakhi, T.; Matsoukas, M.T.; Hayes, A.; Rybalka, E.; Caprnda, M.; Rimarova, K.; Sepsi, M.; Büsselberg, D.; Kruzliak, P.; Matsoukas, J.; et al. Alamandine Reverses Hyperhomocysteinemia-induced Vascular Dysfunction via PKA-dependent Mechanisms. Cardiovasc. Ther. 2017, 35, e12306. [Google Scholar] [CrossRef]
  12. Weber, M.A. The Angiotensin II Receptor Blockers: Opportunities across the Spectrum of Cardiovascular Disease. Rev. Cardiovasc. Med. 2002, 3, 183–191. [Google Scholar]
  13. Cavalli, A.; Bolognesi, M.L.; Minarini, A.; Rosini, M.; Tumiatti, V.; Recanatini, M.; Melchiorre, C. Multi-Target-Directed Ligands To Combat Neurodegenerative Diseases. J. Med. Chem. 2008, 51, 347–372. [Google Scholar] [CrossRef]
  14. Brindisi, M.; Kessler, S.M.; Kumar, V.; Zwergel, C. Editorial: Multi-Target Directed Ligands for the Treatment of Cancer. Front. Oncol. 2022, 12, 980141. [Google Scholar] [CrossRef]
  15. Makhoba, X.H.; Viegas, C., Jr.; Mosa, R.A.; Viegas, F.P.; Pooe, O.J. Potential Impact of the Multi-Target Drug Approach in the Treatment of Some Complex Diseases. Drug Des. Dev. Ther. 2020, 14, 3235–3249. [Google Scholar] [CrossRef]
  16. Kumar, B.; Thakur, A.; Dwivedi, A.R.; Kumar, R.; Kumar, V. Multi-Target-Directed Ligands as an Effective Strategy for the Treatment of Alzheimer’s Disease. Curr. Med. Chem. 2022, 29, 1757–1803. [Google Scholar] [CrossRef]
  17. Ciociola, A.A.; Cohen, L.B.; Kulkarni, P.; Kefalas, C.; Buchman, A.; Burke, C.; Cain, T.; Connor, J.; Ehrenpreis, E.D.; Fang, J.; et al. How Drugs Are Developed and Approved by the FDA: Current Process and Future Directions. Am. J. Gastroenterol. 2014, 109, 620–623. [Google Scholar] [CrossRef]
  18. Tamimi, N.A.M.; Ellis, P. Drug Development: From Concept to Marketing! Nephron Clin. Pract. 2009, 113, c125–c131. [Google Scholar] [CrossRef]
  19. Tonkens, R. An Overview of the Drug Development Process. Physician Exec. 2005, 31, 48–52. [Google Scholar]
  20. Brodniewicz, T.; Grynkiewicz, G. Preclinical Drug Development. Acta Pol. Pharm. 2010, 67, 578–585. [Google Scholar]
  21. Singh, G. Preclinical Drug Development. In Pharmaceutical Medicine and Translational Clinical Research; Elsevier: London, UK, 2018; pp. 47–63. ISBN 978-0-12-802103-3. [Google Scholar]
  22. Pushpakom, S.; Iorio, F.; Eyers, P.A.; Escott, K.J.; Hopper, S.; Wells, A.; Doig, A.; Guilliams, T.; Latimer, J.; McNamee, C.; et al. Drug Repurposing: Progress, Challenges and Recommendations. Nat. Rev. Drug Discov. 2019, 18, 41–58. [Google Scholar] [CrossRef]
  23. Korth-Bradley, J.M. Regulatory Framework for Drug Development in Rare Diseases. J. Clin. Pharmacol. 2022, 62, S15–S26. [Google Scholar] [CrossRef]
  24. Fetro, C.; Scherman, D. Drug Repurposing in Rare Diseases: Myths and Reality. Therapies 2020, 75, 157–160. [Google Scholar] [CrossRef]
  25. Réda, C.; Vie, J.-J.; Wolkenhauer, O. Comprehensive Evaluation of Pure and Hybrid Collaborative Filtering in Drug Repurposing. Sci. Rep. 2025, 15, 2711. [Google Scholar] [CrossRef]
  26. Ghofrani, H.A.; Osterloh, I.H.; Grimminger, F. Sildenafil: From Angina to Erectile Dysfunction to Pulmonary Hypertension and Beyond. Nat. Rev. Drug Discov. 2006, 5, 689–702. [Google Scholar] [CrossRef]
  27. Ignarro, L.J.; Bush, P.A.; Buga, G.M.; Wood, K.S.; Fukuto, J.M.; Rajfer, J. Nitric Oxide and Cyclic GMP For-mation upon Electrical Field Stimulation Cause Relaxation of Corpus Cavernosum Smooth Muscle. Biochem. Biophys. Res. Commun. 1990, 170, 843–850. [Google Scholar] [CrossRef]
  28. Baldaçara, L. Duloxetine: An Update. Res. Soc. Dev. 2024, 13, 1–9. [Google Scholar] [CrossRef]
  29. Goldstein, D.J. Duloxetine in the Treatment of Major Depressive Disorder. Neuropsychiatr. Dis. Treat. 2007, 3, 193–209. [Google Scholar] [CrossRef]
  30. Lunn, M.P.; Hughes, R.A.; Wiffen, P.J. Duloxetine for Treating Painful Neuropathy, Chronic Pain or Fibromyalgia. Cochrane Database Syst. Rev. 2014, 1, CD007115. [Google Scholar] [CrossRef]
  31. Khan, A.Y.; Macaluso, M. Duloxetine for the Treatment of Generalized Anxiety Disorder: A Review. Neuropsychiatr. Dis. Treat. 2009, 5, 23–31. [Google Scholar] [CrossRef]
  32. Gao, S.-H.; Huo, J.-B.; Pan, Q.-M.; Li, X.-W.; Chen, H.-Y.; Huang, J.-H. The Short-Term Effect and Safety of Duloxetine in Osteoarthritis: A Systematic Review and Meta-Analysis. Medicine 2019, 98, e17541. [Google Scholar] [CrossRef]
  33. Mangır, N.; Uçar, M.; Gülpınar, Ö.; Özkürkçügil, C.; Demirkesen, O.; Tarcan, T. Duloxetine in the Treatment of Women with Urinary Incontinence: A Systematic Review and Meta-Analysis of Efficacy Data from Randomized Controlled Clinical Trials. J. Urol. Surg. 2023, 10, 1–8. [Google Scholar] [CrossRef]
  34. Wong, D.T.; Perry, K.W.; Bymaster, F.P. The Discovery of Fluoxetine Hydrochloride (Prozac). Nat. Rev. Drug Discov. 2005, 4, 764–774. [Google Scholar] [CrossRef]
  35. Romano, S.; Judge, R.; Dillon, J.; Shuler, C.; Sundell, K. The Role of Fluoxetine in the Treatment of Premenstrual Dysphoric Disorder. Clin. Ther. 1999, 21, 615–633. [Google Scholar] [CrossRef]
  36. Warner, C.B.; Ottman, A.A.; Brown, J.N. The Role of Atomoxetine for Parkinson Disease–Related Executive Dysfunction: A Systematic Review. J. Clin. Psychopharmacol. 2018, 38, 627–631. [Google Scholar] [CrossRef]
  37. Dell’Agnello, G.; Maschietto, D.; Bravaccio, C.; Calamoneri, F.; Masi, G.; Curatolo, P.; Besana, D.; Mancini, F.; Rossi, A.; Poole, L.; et al. Atomoxetine Hydrochloride in the Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder and Comorbid Oppositional Defiant Disorder: A Placebo-Controlled Italian Study. Eur. Neuropsychopharmacol. 2009, 19, 822–834. [Google Scholar] [CrossRef]
  38. Parkes, J.D.; Marsden, C.D.; Donaldson, I.; Galea-Debono, A.; Walters, J.; Kennedy, G.; Asselman, P. Bromocriptine Treatment in Parkinson’s Disease. J. Neurol. Neurosurg. Psychiatry 1976, 39, 184–193. [Google Scholar] [CrossRef]
  39. DeFronzo, R.A. Bromocriptine: A Sympatholytic, D2-Dopamine Agonist for the Treatment of Type 2 Diabetes. Diabetes Care 2011, 34, 789–794, Erratum in Diabetes Care 2011, 34, 1442. [Google Scholar] [CrossRef]
  40. Cho, K.R.; Jo, K.-I.; Shin, H.J. Bromocriptine Therapy for the Treatment of Invasive Prolactinoma: The Single Institute Experience. Brain Tumor Res. Treat. 2013, 1, 71–77. [Google Scholar] [CrossRef]
  41. Ciapparelli, A.; Dell’Osso, L.; Pini, S.; Chiavacci, M.C.; Fenzi, M.; Cassano, G.B. Clozapine for Treatment-Refractory Schizophrenia, Schizoaffective Disorder, and Psychotic Bipolar Disorder: A 24-Month Naturalistic Study. J. Clin. Psychiatry 2000, 61, 329–334. [Google Scholar] [CrossRef]
  42. Pu, Y.; Xu, F.; He, A.; Li, R.; Wang, X.; Zhou, L.; Sun, H.; Zhang, Y.; Xia, Y. Repurposing Chlorpromazine for the Treatment of Triple-Negative Breast Cancer Growth and Metastasis Based on Modulation of Mitochondria-Mediated Apoptosis and Autophagy/Mitophagy. Br. J. Cancer 2025, 132, 997–1009. [Google Scholar] [CrossRef] [PubMed]
  43. Licht, R.W. Lithium: Still a Major Option in the Management of Bipolar Disorder. CNS Neurosci. Ther. 2012, 18, 219–226. [Google Scholar] [CrossRef] [PubMed]
  44. Ge, W.; Jakobsson, E. Systems Biology Understanding of the Effects of Lithium on Cancer. Front. Oncol. 2019, 9, 296. [Google Scholar] [CrossRef] [PubMed]
  45. Chatupheeraphat, C.; Kaewsai, N.; Anuwongcharoen, N.; Phanus-umporn, C.; Pornsuwan, S.; Eiamphungporn, W. Penfluridol Synergizes with Colistin to Reverse Colistin Resistance in Gram-Negative Bacilli. Sci. Rep. 2025, 15, 16114. [Google Scholar] [CrossRef]
  46. Ali Ibrahim Mze, A.; Abdul Rahman, A. Repurposing the Antipsychotic Drug Penfluridol for Cancer Treatment (Review). Oncol. Rep. 2024, 52, 174. [Google Scholar] [CrossRef]
  47. Parker, S.G.; Raval, P.; Yeulet, S.; Eden, R.J. Tolerance to Peripheral, but Not Central, Effects of Ropinirole, a Selective Dopamine D2-like Receptor Agonist. Eur. J. Pharmacol. 1994, 265, 17–26. [Google Scholar] [CrossRef]
  48. Zhu, J.; Chen, M. The Effect and Safety of Ropinirole in the Treatment of Parkinson Disease: A Systematic Review and Meta-Analysis. Medicine 2021, 100, e27653. [Google Scholar] [CrossRef]
  49. Werz, O.; Stettler, H.; Theurer, C.; Seibel, J. The 125th Anniversary of Aspirin—The Story Continues. Pharmaceuticals 2024, 17, 437. [Google Scholar] [CrossRef]
  50. Undas, A.; Brummel-Ziedins, K.E.; Mann, K.G. Antithrombotic Properties of Aspirin and Resistance to Aspirin: Beyond Strictly Antiplatelet Actions. Blood 2007, 109, 2285–2292. [Google Scholar] [CrossRef]
  51. Clemett, D.; Goa, K.L. Celecoxib: A Review of Its Use in Osteoarthritis, Rheumatoid Arthritis and Acute Pain. Drugs 2000, 59, 957–980. [Google Scholar] [CrossRef]
  52. Lynch, P.M.; Ayers, G.D.; Hawk, E.; Richmond, E.; Eagle, C.; Woloj, M.; Church, J.; Hasson, H.; Patterson, S.; Half, E.; et al. The Safety and Efficacy of Celecoxib in Children With Familial Adenomatous Polyposis. Am. J. Gastroenterol. 2010, 105, 1437–1443. [Google Scholar] [CrossRef]
  53. Edwards, J.E.; Moore, R.A. Finasteride in the Treatment of Clinical Benign Prostatic Hyperplasia: A Systematic Review of Randomised Trials. BMC Urol. 2002, 2, 14. [Google Scholar] [CrossRef]
  54. Gupta, A.K.; Venkataraman, M.; Talukder, M.; Bamimore, M.A. Finasteride for Hair Loss: A Review. J. Dermatol. Treat. 2022, 33, 1938–1946. [Google Scholar] [CrossRef] [PubMed]
  55. Simpson, K.L.; McClellan, K.J. Losartan: A Review of Its Use, with Special Focus on Elderly Patients. Drugs Aging 2000, 16, 227–250. [Google Scholar] [CrossRef] [PubMed]
  56. Nyström, A.; Thriene, K.; Mittapalli, V.; Kern, J.S.; Kiritsi, D.; Dengjel, J.; Bruckner-Tuderman, L. Losartan Ameliorates Dystrophic Epidermolysis Bullosa and Uncovers New Disease Mechanisms. EMBO Mol. Med. 2015, 7, 1211–1228. [Google Scholar] [CrossRef] [PubMed]
  57. Rahmani, W.; Chung, H.; Sinha, S.; Bui-Marinos, M.P.; Arora, R.; Jaffer, A.; Corcoran, J.A.; Biernaskie, J.; Chun, J. Attenuation of SARS-CoV-2 Infection by Losartan in Human Kidney Organoids. iScience 2022, 25, 103818. [Google Scholar] [CrossRef]
  58. Mehta, P.K. Severe Hypertension: Treatment with Minoxidil. JAMA 1975, 233, 249. [Google Scholar] [CrossRef]
  59. Randolph, M.; Tosti, A. Oral Minoxidil Treatment for Hair Loss: A Review of Efficacy and Safety. J. Am. Acad. Dermatol. 2021, 84, 737–746. [Google Scholar] [CrossRef]
  60. Hicks, C.; Gulick, R.M. Raltegravir: The First HIV Type 1 Integrase Inhibitor. Clin Infect. Dis. 2009, 48, 931–939. [Google Scholar] [CrossRef]
  61. Alburquerque-González, B.; Bernabé-García, Á.; Bernabé-García, M.; Ruiz-Sanz, J.; López-Calderón, F.F.; Gonnelli, L.; Banci, L.; Peña-García, J.; Luque, I.; Nicolás, F.J.; et al. The FDA-Approved Antiviral Raltegravir Inhibits Fascin1-Dependent Invasion of Colorectal Tumor Cells In Vitro and In Vivo. Cancers 2021, 13, 861. [Google Scholar] [CrossRef]
  62. Broder, S. The Development of Antiretroviral Therapy and Its Impact on the HIV-1/AIDS Pandemic. Antivir. Res. 2010, 85, 1–18. [Google Scholar] [CrossRef]
  63. Langtry, H.D.; Campoli-Richards, D.M. Zidovudine: A Review of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy. Drugs 1989, 37, 408–450. [Google Scholar] [CrossRef]
  64. Yamashita, M. Auranofin: Past to Present, and Repurposing. Int. Immunopharmacol. 2021, 101, 108272. [Google Scholar] [CrossRef]
  65. Pessetto, Z.Y.; Weir, S.J.; Sethi, G.; Broward, M.A.; Godwin, A.K. Drug Repurposing for Gastrointestinal Stromal Tumor. Mol. Cancer Ther. 2013, 12, 1299–1309. [Google Scholar] [CrossRef]
  66. Merino, M.; Kasamon, Y.; Li, H.; Ma, L.; Leong, R.; Zhou, J.; Reaman, G.; Chambers, W.; Richardson, N.; Theoret, M.; et al. FDA Approval Summary: Crizotinib for Pediatric and Young Adult Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma. Pediatr. Blood Cancer 2022, 69, e29602. [Google Scholar] [CrossRef]
  67. Roberts, P.J. Clinical Use of Crizotinib for the Treatment of Non-Small Cell Lung Cancer. Biologics 2013, 7, 91–101. [Google Scholar] [CrossRef]
  68. Sacha, T. Imatinib in Chronic Myeloid Leukemia: An Overview. Mediterr. J. Hematol. Infect. Dis. 2014, 6, e2014007. [Google Scholar] [CrossRef]
  69. Lopes, L.F.; Bacchi, C.E. Imatinib Treatment for Gastrointestinal Stromal Tumour (GIST). J. Cell. Mol. Med. 2010, 14, 42–50. [Google Scholar] [CrossRef]
  70. Fujita, K.; Kubota, Y.; Ishida, H.; Sasaki, Y. Irinotecan, a Key Chemotherapeutic Drug for Metastatic Colorectal Cancer. World J. Gastroenterol. 2015, 21, 12234–12248. [Google Scholar] [CrossRef]
  71. Brown, M.B.; Blair, H.A. Liposomal Irinotecan: A Review as First-Line Therapy in Metastatic Pancreatic Adenocarcinoma. Drugs 2025, 85, 255–262. [Google Scholar] [CrossRef]
  72. Bailey, C.J. Metformin: Therapeutic Profile in the Treatment of Type 2 Diabetes. Diabetes Obes. Metab. 2024, 26, 3–19. [Google Scholar] [CrossRef] [PubMed]
  73. Van Eijck, C.W.F.; Vadgama, D.; Van Eijck, C.H.J.; Wilmink, J.W.; for the Dutch Pancreatic Cancer Group (DPCG). Metformin Boosts Antitumor Immunity and Improves Prognosis in Upfront Resected Pancreatic Cancer: An Observational Study. JNCI J. Natl. Cancer Inst. 2024, 116, 1374–1383. [Google Scholar] [CrossRef] [PubMed]
  74. Lee, T.Y.; Martinez-Outschoorn, U.E.; Schilder, R.J.; Kim, C.H.; Richard, S.D.; Rosenblum, N.G.; Johnson, J.M. Metformin as a Therapeutic Target in Endometrial Cancers. Front. Oncol. 2018, 8, 341. [Google Scholar] [CrossRef] [PubMed]
  75. Higurashi, T.; Nakajima, A. Metformin and Colorectal Cancer. Front. Endocrinol. 2018, 9, 622. [Google Scholar] [CrossRef] [PubMed]
  76. Tang, J.-C.; An, R.; Jiang, Y.-Q.; Yang, J. Effects and Mechanisms of Metformin on the Proliferation of Esophageal Cancer Cells In Vitro and In Vivo. Cancer Res. Treat. 2017, 49, 778–789. [Google Scholar] [CrossRef]
  77. Wallet, M.A.; Reist, C.M.; Williams, J.C.; Appelberg, S.; Guiulfo, G.L.; Gardner, B.; Sleasman, J.W.; Goodenow, M.M. The HIV-1 Protease Inhibitor Nelfinavir Activates PP2 and Inhibits MAPK Signaling in Macrophages: A Pathway to Reduce Inflammation. J. Leukoc. Biol. 2012, 92, 795–805. [Google Scholar] [CrossRef]
  78. Subeha, M.R.; Telleria, C.M. The Anti-Cancer Properties of the HIV Protease Inhibitor Nelfinavir. Cancers 2020, 12, 3437. [Google Scholar] [CrossRef]
  79. D’Amelio, P.; Isaia, G.C. The Use of Raloxifene in Osteoporosis Treatment. Expert Opin. Pharmacother. 2013, 14, 949–956. [Google Scholar] [CrossRef]
  80. Moen, M.D.; Keating, G.M. Raloxifene: A Review of Its Use in the Prevention of Invasive Breast Cancer. Drugs 2008, 68, 2059–2083. [Google Scholar] [CrossRef]
  81. Pierpont, T.M.; Limper, C.B.; Richards, K.L. Past, Present, and Future of Rituximab—The World’s First Oncology Monoclonal Antibody Therapy. Front. Oncol. 2018, 8, 163. [Google Scholar] [CrossRef]
  82. Cohen, M.D.; Keystone, E. Rituximab for Rheumatoid Arthritis. Rheumatol. Ther. 2015, 2, 99–111. [Google Scholar] [CrossRef]
  83. Rizzo, M.; Porta, C. Sunitinib in the Treatment of Renal Cell Carcinoma: An Update on Recent Evidence. Ther. Adv. Urol. 2017, 9, 195–207. [Google Scholar] [CrossRef] [PubMed]
  84. Mulet-Margalef, N.; Garcia-Del-Muro, X. Sunitinib in the Treatment of Gastrointestinal Stromal Tumor: Patient Selection and Perspectives. Onco Targets Ther. 2016, 9, 7573–7582. [Google Scholar] [CrossRef] [PubMed]
  85. Raymond, E.; Dahan, L.; Raoul, J.-L.; Bang, Y.-J.; Borbath, I.; Lombard-Bohas, C.; Valle, J.; Metrakos, P.; Smith, D.; Vinik, A.; et al. Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors. N. Engl. J. Med. 2011, 364, 501–513, Correction in N. Engl. J. Med. 2011, 364, 1082. [Google Scholar] [CrossRef] [PubMed]
  86. Camejo, N.; Castillo, C.; Alonso, R.; Correa, F.; Rivero, E.; Mezquita, C.; Rosich, A.; Dellacasa, F.; Silveira, L.; Delgado, L. Effectiveness of Trastuzumab for Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer in a Real-Life Setting: One Decade of Experience Under National Treatment Coverage Regulations. JCO Glob. Oncol. 2020, 6, 217–223. [Google Scholar] [CrossRef]
  87. Jeyakumar, A.; Younis, T. Trastuzumab for HER2-Positive Metastatic Breast Cancer: Clinical and Economic Considerations. Clin. Med. Insights Oncol. 2012, 6, 179–187. [Google Scholar] [CrossRef]
  88. Gunturu, K.S.; Woo, Y.; Beaubier, N.; Remotti, H.E.; Saif, M.W. Gastric Cancer and Trastuzumab: First Biologic Therapy in Gastric Cancer. Ther. Adv. Med. Oncol. 2013, 5, 143–151. [Google Scholar] [CrossRef]
  89. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Trastuzumab for Early-Stage, HER2-Positive Breast Cancer: A Meta-Analysis of 13 864 Women in Seven Randomised Trials. Lancet Oncol. 2021, 22, 1139–1150. [Google Scholar] [CrossRef]
  90. Kwitkowski, V.E.; Prowell, T.M.; Ibrahim, A.; Farrell, A.T.; Justice, R.; Mitchell, S.S.; Sridhara, R.; Pazdur, R. FDA Approval Summary: Temsirolimus as Treatment for Advanced Renal Cell Carcinoma. Oncologist 2010, 15, 428–435. [Google Scholar] [CrossRef]
  91. Chang, H.-W.; Wu, M.-J.; Lin, Z.-M.; Wang, C.-Y.; Cheng, S.-Y.; Lin, Y.-K.; Chow, Y.-H.; Ch’ang, H.-J.; Chang, V.H.S. Therapeutic Effect of Repurposed Temsirolimus in Lung Adenocarcinoma Model. Front. Pharmacol. 2018, 9, 778. [Google Scholar] [CrossRef]
  92. Mesa-Arango, A.C.; Scorzoni, L.; Zaragoza, O. It Only Takes One to Do Many Jobs: Amphotericin B as Antifungal and Immunomodulatory Drug. Front. Microbiol. 2012, 3, 286. [Google Scholar] [CrossRef]
  93. Balasegaram, M.; Ritmeijer, K.; Lima, M.A.; Burza, S.; Ortiz Genovese, G.; Milani, B.; Gaspani, S.; Potet, J.; Chappuis, F. Liposomal Amphotericin B as a Treatment for Human Leishmaniasis. Expert Opin. Emerg. Drugs 2012, 17, 493–510. [Google Scholar] [CrossRef]
  94. Hirabayashi, K.E.; Kalin-Hajdu, E.; Brodie, F.L.; Kersten, R.C.; Russell, M.S.; Vagefi, M.R. Retrobulbar Injection of Amphotericin B for Orbital Mucormycosis. Ophthalmic Plast. Reconstr. Surg. 2017, 33, e94–e97. [Google Scholar] [CrossRef]
  95. Liu, G.; Yin, Y.; Zhang, L.; He, D.; Yang, L. Efficacy of Dapoxetine in the Treatment of Patients With Lifelong Premature Ejaculation as an Alternative to Sertraline Therapy. Sex. Med. 2022, 10, 100473-1. [Google Scholar] [CrossRef]
  96. Zhang, B.; Yu, J.; Zhu, G.; Huang, Y.; Zhang, K.; Xiao, X.; He, W.; Yuan, J.; Gao, X. Dapoxetine, a Selective Serotonin Reuptake Inhibitor, Suppresses Zika Virus Infection In Vitro. Molecules 2023, 28, 8142. [Google Scholar] [CrossRef] [PubMed]
  97. Yee, M.-L.; Tan, H.-H. Use of Everolimus in Liver Transplantation. World J. Hepatol. 2017, 9, 990–1000. [Google Scholar] [CrossRef] [PubMed]
  98. Medici, B.; Caffari, E.; Maculan, Y.; Benatti, S.; Piacentini, F.; Dominici, M.; Gelsomino, F. Everolimus in the Treatment of Neuroendocrine Tumors: Lights and Shadows. Biomedicines 2025, 13, 455. [Google Scholar] [CrossRef] [PubMed]
  99. Coppin, C. Everolimus: The First Approved Product for Patients with Advanced Renal Cell Cancer after Sunitinib and/or Sorafenib. Biologics 2010, 4, 91–101. [Google Scholar] [CrossRef]
  100. Krueger, D.A.; Care, M.M.; Holland, K.; Agricola, K.; Tudor, C.; Mangeshkar, P.; Wilson, K.A.; Byars, A.; Sahmoud, T.; Franz, D.N. Everolimus for Subependymal Giant-Cell Astrocytomas in Tuberous Sclerosis. N. Engl. J. Med. 2010, 363, 1801–1811. [Google Scholar] [CrossRef]
  101. Shiraki, K.; Daikoku, T. Favipiravir, an Anti-Influenza Drug against Life-Threatening RNA Virus Infections. Pharmacol. Ther. 2020, 209, 107512. [Google Scholar] [CrossRef]
  102. Boretti, A. Favipiravir Use for SARS-CoV-2 Infection. Pharmacol. Rep. 2020, 72, 1542–1552. [Google Scholar] [CrossRef]
  103. Crump, A. Ivermectin: Enigmatic Multifaceted ‘Wonder’ Drug Continues to Surprise and Exceed Expectations. J. Antibiot. 2017, 70, 495–505. [Google Scholar] [CrossRef]
  104. Formiga, F.R.; Leblanc, R.; De Souza Rebouças, J.; Farias, L.P.; De Oliveira, R.N.; Pena, L. Ivermectin: An Award-Winning Drug with Expected Antiviral Activity against COVID-19. J. Control. Release 2021, 329, 758–761. [Google Scholar] [CrossRef]
  105. Heel, R.C.; Brogden, R.N.; Carmine, A.; Morley, P.A.; Speight, T.M.; Avery, G.S. Ketoconazole: A Review of Its Therapeutic Efficacy in Superficial and Systemic Fungal Infections. Drugs 1982, 23, 1–36. [Google Scholar] [CrossRef] [PubMed]
  106. Loli, P.; Berselli, M.E.; Tagliaferri, M. Use of Ketoconazole in the Treatment of Cushing’s Syndrome. J. Clin. Endocrinol. Metab. 1986, 63, 1365–1371. [Google Scholar] [CrossRef] [PubMed]
  107. Bakheit, A.H.; Darwish, H.; Darwish, I.A.; Al-Ghusn, A.I. Remdesivir. In Profiles of Drug Substances, Excipients and Related Methodology; Elsevier: London, UK, 2023; Volume 48, pp. 71–108. ISBN 978-0-443-19382-8. [Google Scholar]
  108. Jeon, H.J.; Lee, H.-E.; Yang, J. Safety and Efficacy of Rapamune® (Sirolimus) in Kidney Transplant Recipients: Results of a Prospective Post-Marketing Surveillance Study in Korea. BMC Nephrol. 2018, 19, 201. [Google Scholar] [CrossRef] [PubMed]
  109. Mejia, P.; Treviño-Villarreal, J.H.; Reynolds, J.S.; De Niz, M.; Thompson, A.; Marti, M.; Mitchell, J.R. A Single Rapamycin Dose Protects against Late-Stage Experimental Cerebral Malaria via Modulation of Host Immunity, Endothelial Activation and Parasite Sequestration. Malar. J. 2017, 16, 455. [Google Scholar] [CrossRef]
  110. Okafor, M.C. Thalidomide for Erythema Nodosum Leprosum and Other Applications. Pharmacotherapy 2003, 23, 481–493. [Google Scholar] [CrossRef]
  111. Latif, T.; Chauhan, N.; Khan, R.; Moran, A.; Usmani, S.Z. Thalidomide and Its Analogues in the Treatment of Multiple Myeloma. Exp. Hematol. Oncol. 2012, 1, 27. [Google Scholar] [CrossRef]
  112. Jenneck, C.; Novak, N. The Safety and Efficacy of Alefacept in the Treatment of Chronic Plaque Psoriasis. Ther. Clin. Risk Manag. 2007, 3, 411–420. [Google Scholar]
  113. Zaidi, A.; Meng, Q. Can We Repurpose FDA-Approved Alefacept to Diminish the HIV Reservoir? Immunother. Open Acc. 2016, 1, 1000104. [Google Scholar] [CrossRef]
  114. Hwang, Y.J.; Chang, A.R.; Brotman, D.J.; Inker, L.A.; Grams, M.E.; Shin, J. Baclofen and the Risk of Fall and Fracture in Older Adults: A Real-world Cohort Study. J. Am. Geriatr. Soc. 2024, 72, 91–101. [Google Scholar] [CrossRef]
  115. de Beaurepaire, R.; Sinclair, J.M.A.; Heydtmann, M.; Addolorato, G.; Aubin, H.-J.; Beraha, E.M.; Caputo, F.; Chick, J.D.; de La Selle, P.; Franchitto, N.; et al. The Use of Baclofen as a Treatment for Alcohol Use Disorder: A Clinical Practice Perspective. Front. Psychiatry 2018, 9, 708. [Google Scholar] [CrossRef]
  116. Feldman, S.R.; Yentzer, B.A. Topical Clobetasol Propionate in the Treatment of Psoriasis: A Review of Newer Formulations. Am. J. Clin. Dermatol. 2009, 10, 397–406. [Google Scholar] [CrossRef]
  117. Azhar, S.D.; Shahid, N.; Sadiq, A.; Khan, A.W.; Sultan Dar, M.; Fadlalla Ahmed, T.K. Clobetasol Propionate for Post-Cataract Surgery Pain and Inflammation. Ann. Med. Surg. 2024, 86, 6395–6398. [Google Scholar] [CrossRef] [PubMed]
  118. Mills, E.A.; Ogrodnik, M.A.; Plave, A.; Mao-Draayer, Y. Emerging Understanding of the Mechanism of Action for Dimethyl Fumarate in the Treatment of Multiple Sclerosis. Front. Neurol. 2018, 9, 5. [Google Scholar] [CrossRef] [PubMed]
  119. Burlando, M.; Campione, E.; Cuccia, A.; Malara, G.; Naldi, L.; Prignano, F.; Zichichi, L. Real-World Use of Dimethyl Fumarate in Patients with Plaque Psoriasis: A Delphi-Based Expert Consensus. Dermatol. Rep. 2023, 15, 9613. [Google Scholar] [CrossRef]
  120. McGuire, V.A.; Ruiz-Zorrilla Diez, T.; Emmerich, C.H.; Strickson, S.; Ritorto, M.S.; Sutavani, R.V.; Weiβ, A.; Houslay, K.F.; Knebel, A.; Meakin, P.J.; et al. Dimethyl Fumarate Blocks Pro-Inflammatory Cytokine Production via Inhibition of TLR Induced M1 and K63 Ubiquitin Chain Formation. Sci. Rep. 2016, 6, 31159. [Google Scholar] [CrossRef]
  121. Hayat, A.; Haria, D.; Salifu, M.O. Erythropoietin Stimulating Agents in the Management of Anemia of Chronic Kidney Disease. Patient Prefer. Adherence 2008, 2, 195–200. [Google Scholar] [CrossRef]
  122. Skrifvars, M.B.; Luethi, N.; Bailey, M.; French, C.; Nichol, A.; Trapani, T.; McArthur, C.; Arabi, Y.M.; Bendel, S.; Cooper, D.J.; et al. The Effect of Recombinant Erythropoietin on Long-Term Outcome after Moderate-to-Severe Traumatic Brain Injury. Intensive Care Med. 2023, 49, 831–839. [Google Scholar] [CrossRef]
  123. Dowlut-McElroy, T.; Shankar, R.K. The Care of Adolescents and Young Adults with Turner Syndrome: A Pediatric and Adolescent Gynecology Perspective. J. Pediatr. Adolesc. Gynecol. 2022, 35, 429–434. [Google Scholar] [CrossRef]
  124. Likis, F.E. CONTRACEPTIVE APPLICATIONS OF ESTROGEN. J. Midwifery Women’s Health 2002, 47, 139–156. [Google Scholar] [CrossRef]
  125. Franks, S.; Layton, A.; Glasier, A. Cyproterone Acetate/Ethinyl Estradiol for Acne and Hirsutism: Time to Revise Prescribing Policy. Hum. Reprod. 2007, 23, 231–232. [Google Scholar] [CrossRef]
  126. Pelletier, D.; Hafler, D.A. Fingolimod for Multiple Sclerosis. N. Engl. J. Med. 2012, 366, 339–347. [Google Scholar] [CrossRef]
  127. Leßmann, V.; Kartalou, G.-I.; Endres, T.; Pawlitzki, M.; Gottmann, K. Repurposing Drugs against Alzheimer’s Disease: Can the Anti-Multiple Sclerosis Drug Fingolimod (FTY720) Effectively Tackle Inflammation Processes in AD? J. Neural Transm. 2023, 130, 1003–1012. [Google Scholar] [CrossRef] [PubMed]
  128. Patmanathan, S.N.; Yap, L.F.; Murray, P.G.; Paterson, I.C. The Antineoplastic Properties of FTY720: Evidence for the Repurposing of Fingolimod. J. Cell. Mol. Med. 2015, 19, 2329–2340. [Google Scholar] [CrossRef] [PubMed]
  129. Gesualdo, C.; Balta, C.; Platania, C.B.M.; Trotta, M.C.; Herman, H.; Gharbia, S.; Rosu, M.; Petrillo, F.; Giunta, S.; Della Corte, A.; et al. Fingolimod and Diabetic Retinopathy: A Drug Repurposing Study. Front. Pharmacol. 2021, 12, 718902. [Google Scholar] [CrossRef] [PubMed]
  130. Iepsen, E.W.; Torekov, S.S.; Holst, J.J. Liraglutide for Type 2 Diabetes and Obesity: A 2015 Update. Expert Rev. Cardiovasc. Ther. 2015, 13, 753–767. [Google Scholar] [CrossRef] [PubMed]
  131. Edison, P.; Femminella, G.D.; Ritchie, C.W.; Holmes, C.; Walker, Z.; Ridha, B.H.; Raza, S.; Livingston, N.R.; Nowell, J.; Busza, G.; et al. Evaluation of Liraglutide in the Treatment of Alzheimer’s Disease. Alzheimer’s Dement. 2021, 17, e057848. [Google Scholar] [CrossRef]
  132. Sadowska, A.M. N.-Acetylcysteine Mucolysis in the Management of Chronic Obstructive Pulmonary Disease. Ther. Adv. Respir. Dis. 2012, 6, 127–135. [Google Scholar] [CrossRef]
  133. Carollo, M.; Carollo, N.; Montan, G. The Promise of N-Acetylcysteine in the Treatment of Obsessive-Compulsive Disorder. CNS Neurosci. Ther. 2024, 30, e14653. [Google Scholar] [CrossRef] [PubMed]
  134. Derry, S.; Bell, R.F.; Straube, S.; Wiffen, P.J.; Aldington, D.; Moore, R.A. Pregabalin for Neuropathic Pain in Adults. Cochrane Database Syst. Rev. 2019, 1, CD007076. [Google Scholar] [CrossRef] [PubMed]
  135. Baldwin, D.S.; Ajel, K.; Masdrakis, V.G.; Nowak, M.; Rafiq, R. Pregabalin for the Treatment of Generalized Anxiety Disorder: An Update. Nephrol. Dial. Transplant. 2013, 9, 883–892. [Google Scholar] [CrossRef] [PubMed]
  136. Taylor, F.; Huffman, M.D.; Macedo, A.F.; Moore, T.H.M.; Burke, M.; Davey Smith, G.; Ward, K.; Ebrahim, S. Statins for the Primary Prevention of Cardiovascular Disease. Cochrane Database Syst. Rev. 2013, 2013, CD004816. [Google Scholar] [CrossRef]
  137. Tripathi, S.; Gupta, E.; Galande, S. Statins as Anti-Tumor Agents: A Paradigm for Repurposed Drugs. Cancer Rep. 2024, 7, e2078. [Google Scholar] [CrossRef]
  138. Bhat, A.; Dalvi, H.; Jain, H.; Rangaraj, N.; Singh, S.B.; Srivastava, S. Perspective Insights of Repurposing the Pleiotropic Efficacy of Statins in Neurodegenerative Disorders: An Expository Appraisal. Curr. Res. Pharmacol. Drug Discov. 2021, 2, 100012. [Google Scholar] [CrossRef]
  139. Boyle, A.K.; Rinaldi, S.F.; Rossi, A.G.; Saunders, P.T.K.; Norman, J.E. Repurposing Simvastatin as a Therapy for Preterm Labor: Evidence from Preclinical Models. FASEB J. 2019, 33, 2743–2758. [Google Scholar] [CrossRef]
  140. Moglad, E.; Elekhnawy, E.; Alanazi, N.; Al-Fakhrany, O.M. Repurposing Simvastatin for Treatment of Klebsiella Pneumoniae Infections: In Vitro and in Vivo Study. Biofouling 2024, 40, 801–815. [Google Scholar] [CrossRef]
  141. Lyseng-Williamson, K.A.; Yang, L.P.H. Topiramate: A Review of Its Use in the Treatment of Epilepsy. Drugs 2007, 67, 2231–2256. [Google Scholar] [CrossRef]
  142. Wajid, I.; Vega, A.; Thornhill, K.; Jenkins, J.; Merriman, C.; Chandler, D.; Shekoohi, S.; Cornett, E.M.; Kaye, A.D. Topiramate (Topamax): Evolving Role in Weight Reduction Management: A Narrative Review. Life 2023, 13, 1845. [Google Scholar] [CrossRef]
  143. Park, K. A Review of Computational Drug Repurposing. Transl. Clin. Pharmacol. 2019, 27, 59. [Google Scholar] [CrossRef]
  144. Natsheh, I.Y.; Alsaleh, M.M.; Alkhawaldeh, A.K.; Albadawi, D.K.; Darwish, M.M.; Shammout, M.J.A. The Dark Side of Drug Repurposing. From Clinical Trial Challenges to Antimicrobial Resistance: Analysis Based on Three Major Fields. Drug Target Insights 2024, 18, 8–19. [Google Scholar] [CrossRef]
  145. Pandit, J.N.; Kumari, R.; Kumari, M.; Mp, A.R.; Yadav, A.; Arava, S. Rare Fatal Effect of Combined Use of Sildenafil and Alcohol Leading to Cerebrovascular Accident. J. Forensic Leg. Med. 2023, 95, 102504. [Google Scholar] [CrossRef] [PubMed]
  146. Singh, B.; Cusick, A.S.; Goyal, A.; Patel, P. ACE Inhibitors. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2025. [Google Scholar]
  147. Moore, G.J.; Matsoukas, J.M. Angiotensin as a Model for Hormone—Receptor Interactions. Biosci. Rep. 1985, 5, 407–416. [Google Scholar] [CrossRef] [PubMed]
  148. Matsoukas, J.M.; Hondrelis, J.; Keramida, M.; Mavromoustakos, T.; Makriyannis, A.; Yamdagni, R.; Wu, Q.; Moore, G.J. Role of the NH2-Terminal Domain of Angiotensin II (ANG II) and [Sar1]Angiotensin II on Conformation and Activity. NMR Evidence for Aromatic Ring Clustering and Peptide Backbone Folding Compared with [Des-1,2,3]Angiotensin II. J. Biol. Chem. 1994, 269, 5303–5312. [Google Scholar] [CrossRef] [PubMed]
  149. Matsoukas, J.M.; Goghari, M.H.; Scanlon, M.N.; Franklin, K.J.; Moore, G.J. Synthesis and Biological Activities of Analogs of Angiotensins II and III Containing O-Methyltyrosine and D-Tryptophan. J. Med. Chem. 1985, 28, 780–783. [Google Scholar] [CrossRef]
  150. Matsoukas, J.; Cordopatis, P.; Belte, U.; Goghari, M.H.; Ganter, R.C.; Franklin, K.J.; Moore, G.J. Importance of the N-Terminal Domain of the Type II Angiotensin Antagonist Sarmesin for Receptor Blockade. J. Med. Chem. 1988, 31, 1418–1421. [Google Scholar] [CrossRef]
  151. Gaidai, O.; Cao, Y.; Loginov, S. Global Cardiovascular Diseases Death Rate Prediction. Curr. Probl. Cardiol. 2023, 48, 101622. [Google Scholar] [CrossRef]
  152. Chong, B.; Jayabaskaran, J.; Jauhari, S.M.; Chan, S.P.; Goh, R.; Kueh, M.T.W.; Li, H.; Chin, Y.H.; Kong, G.; Anand, V.V.; et al. Global Burden of Cardiovascular Diseases: Projections from 2025 to 2050. Eur. J. Prev. Cardiol. 2024, 32, 1001–1015. [Google Scholar] [CrossRef]
  153. Martin, S.S.; Aday, A.W.; Allen, N.B.; Almarzooq, Z.I.; Anderson, C.A.M.; Arora, P.; Avery, C.L.; Baker-Smith, C.M.; Bansal, N.; Beaton, A.Z.; et al. 2025 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association. Circulation 2025, 151, e41–e660, Correction in Circulation 2025, 151, e1096. [Google Scholar] [CrossRef]
  154. Wu, C.-Y.; Hu, H.-Y.; Chou, Y.-J.; Huang, N.; Chou, Y.-C.; Li, C.-P. High Blood Pressure and All-Cause and Cardiovascular Disease Mortalities in Community-Dwelling Older Adults. Medicine 2015, 94, e2160. [Google Scholar] [CrossRef]
  155. Ettehad, D.; Emdin, C.A.; Kiran, A.; Anderson, S.G.; Callender, T.; Emberson, J.; Chalmers, J.; Rodgers, A.; Rahimi, K. Blood Pressure Lowering for Prevention of Cardiovascular Disease and Death: A Systematic Review and Meta-Analysis. Lancet 2016, 387, 957–967. [Google Scholar] [CrossRef]
  156. McEvoy, J.W.; McCarthy, C.P.; Bruno, R.M.; Brouwers, S.; Canavan, M.D.; Ceconi, C.; Christodorescu, R.M.; Daskalopoulou, S.S.; Ferro, C.J.; Gerdts, E.; et al. 2024 ESC Guidelines for the Management of Elevated Blood Pressure and Hypertension. Eur. Heart J. 2024, 45, 3912–4018. [Google Scholar] [CrossRef] [PubMed]
  157. Conrad, N.; Judge, A.; Tran, J.; Mohseni, H.; Hedgecott, D.; Crespillo, A.P.; Allison, M.; Hemingway, H.; Cleland, J.G.; McMurray, J.J.V.; et al. Temporal Trends and Patterns in Heart Failure Incidence: A Population-Based Study of 4 Million Individuals. Lancet 2018, 391, 572–580. [Google Scholar] [CrossRef] [PubMed]
  158. McDonagh, T.A.; Metra, M.; Adamo, M.; Gardner, R.S.; Baumbach, A.; Böhm, M.; Burri, H.; Butler, J.; Čelutkienė, J.; Chioncel, O.; et al. 2021 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure. Eur. Heart J. 2021, 42, 3599–3726. [Google Scholar] [CrossRef] [PubMed]
  159. Ghionzoli, N.; Gentile, F.; Del Franco, A.M.; Castiglione, V.; Aimo, A.; Giannoni, A.; Burchielli, S.; Cameli, M.; Emdin, M.; Vergaro, G. Current and Emerging Drug Targets in Heart Failure Treatment. Heart Fail. Rev. 2022, 27, 1119–1136. [Google Scholar] [CrossRef]
  160. McDonagh, T.A.; Metra, M.; Adamo, M.; Gardner, R.S.; Baumbach, A.; Böhm, M.; Burri, H.; Butler, J.; Čelutkienė, J.; Chioncel, O.; et al. 2023 Focused Update of the 2021 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure. Eur. Heart J. 2023, 44, 3627–3639. [Google Scholar] [CrossRef]
  161. Kidney Disease: Improving Global Outcomes (KDIGO). CKD Work Group KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024, 105, S117–S314. [Google Scholar] [CrossRef]
  162. Mezzano, S.A.; Ruiz-Ortega, M.; Egido, J. Angiotensin II and Renal Fibrosis. Hypertension 2001, 38, 635–638. [Google Scholar] [CrossRef]
  163. Durvasula, R.V.; Shankland, S.J. The Renin-Angiotensin System in Glomerular Podocytes: Mediator of Glomerulosclerosis and Link to Hypertensive Nephropathy. Curr. Sci. Inc. 2006, 8, 132–138. [Google Scholar] [CrossRef]
  164. Roth, G.A.; Abate, D.; Abate, K.H.; Abay, S.M.; Abbafati, C.; Abbasi, N.; Abbastabar, H.; Abd-Allah, F.; Abdela, J.; Abdelalim, A.; et al. Global, Regional, and National Age-Sex-Specific Mortality for 282 Causes of Death in 195 Countries and Territories, 1980–2017: A Systematic Analysis for the Global Burden of Disease Study 2017. Lancet 2018, 392, 1736–1788, Erratum in Lancet 2018, 392, 2170; Erratum in Lancet 2019, 393, e44. [Google Scholar] [CrossRef]
  165. Roth, G.A.; Nguyen, G.; Forouzanfar, M.H.; Mokdad, A.H.; Naghavi, M.; Murray, C.J.L. Estimates of Global and Regional Premature Cardiovascular Mortality in 2025. Circulation 2015, 132, 1270–1282. [Google Scholar] [CrossRef]
  166. Naghavi, M.; Makela, S.; Foreman, K.; O’Brien, J.; Pourmalek, F.; Lozano, R. Algorithms for Enhancing Public Health Utility of National Causes-of-Death Data. Popul Health Metrics 2010, 8, 9. [Google Scholar] [CrossRef]
  167. Byrne, R.A.; Rossello, X.; Coughlan, J.J.; Barbato, E.; Berry, C.; Chieffo, A.; Claeys, M.J.; Dan, G.-A.; Dweck, M.R.; Galbraith, M.; et al. 2023 ESC Guidelines for the Management of Acute Coronary Syndromes. Eur. Heart J. 2023, 44, 3720–3826. [Google Scholar] [CrossRef] [PubMed]
  168. Dargie, H.J.; Byrne, J. Pathophysiological Aspects of the Renin-Angiotensin-Aldosterone System in Acute Myocardial Infarction. Eur. J. Cardiovasc. Prev. Rehabil. 1995, 2, 389–395. [Google Scholar] [CrossRef] [PubMed]
  169. Yang, X.; Li, Y.; Li, Y.; Ren, X.; Zhang, X.; Hu, D.; Gao, Y.; Xing, Y.; Shang, H. Oxidative Stress-Mediated Atherosclerosis: Mechanisms and Therapies. Front. Physiol. 2017, 8, 600. [Google Scholar] [CrossRef] [PubMed]
  170. Schieffer, B.; Schieffer, E.; Hilfiker-Kleiner, D.; Hilfiker, A.; Kovanen, P.T.; Kaartinen, M.; Nussberger, J.; Harringer, W.; Drexler, H. Expression of Angiotensin II and Interleukin 6 in Human Coronary Atherosclerotic Plaques: Potential Implications for Inflammation and Plaque Instability. Circulation 2000, 101, 1372–1378. [Google Scholar] [CrossRef]
  171. Wang, J.; He, W.; Guo, L.; Zhang, Y.; Li, H.; Han, S.; Shen, D. The ACE2-Ang (1–7)-Mas Receptor Axis Attenuates Cardiac Remodeling and Fibrosis in Post-Myocardial Infarction. Mol. Med. Rep. 2017, 16, 1973–1981. [Google Scholar] [CrossRef]
  172. Xie, J.-X.; Hu, J.; Cheng, J.; Liu, C.; Wei, X. The Function of the ACE2/Ang(1–7)/Mas Receptor Axis of the Renin-Angiotensin System in Myocardial Ischemia Reperfusion Injury. Eur. Rev. Med. Pharmacol. Sci. 2022, 26, 1852–1859. [Google Scholar] [CrossRef]
  173. Evans-Lacko, S.; Aguzzoli, E.; Read, S.; Comas-Herrera, A.; Farina, N. World Alzheimer Report 2024: Global Changes in Attitudes to Dementia; Alzheimer’s Disease International: London, UK, 2024. [Google Scholar]
  174. Chatzipieris, F.P.; Kokkalis, A.; Georgiou, N.; Petsas, E.; Apostolou, E.V.; Vougioukalakis, G.C.; Mavromoustakos, T. New Prospects in the Inhibition of Monoamine Oxidase-B (MAO-B) Utilizing Propargylamine Derivatives for the Treatment of Alzheimer’s Disease: A Review. ACS Omega 2025, 10, 26208–26232. [Google Scholar] [CrossRef]
  175. Liu, P.-P.; Xie, Y.; Meng, X.-Y.; Kang, J.-S. History and Progress of Hypotheses and Clinical Trials for Alzheimer’s Disease. Signal Transduct. Target. Ther. 2019, 4, 29. [Google Scholar] [CrossRef] [PubMed]
  176. Huang, L.-K.; Chao, S.-P.; Hu, C.-J. Clinical Trials of New Drugs for Alzheimer Disease. J. Biomed. Sci. 2020, 27, 18. [Google Scholar] [CrossRef]
  177. Lyu, D.; Lyu, X.; Huang, L.; Fang, B. Effects of Three Kinds of Anti-Amyloid-β Drugs on Clinical, Biomarker, Neuroimaging Outcomes and Safety Indexes: A Systematic Review and Meta-Analysis of Phase II/III Clinical Trials in Alzheimer’s Disease. Ageing Res. Rev. 2023, 88, 101959. [Google Scholar] [CrossRef]
  178. Iadecola, C. The Pathobiology of Vascular Dementia. Neuron 2013, 80, 844–866. [Google Scholar] [CrossRef]
  179. Kisler, K.; Nelson, A.R.; Montagne, A.; Zlokovic, B.V. Cerebral Blood Flow Regulation and Neurovascular Dysfunction in Alzheimer Disease. Nat. Rev. Neurosci. 2017, 18, 419–434. [Google Scholar] [CrossRef]
  180. Royea, J.; Hamel, E. Brain Angiotensin II and Angiotensin IV Receptors as Potential Alzheimer’s Disease Therapeutic Targets. GeroScience 2020, 42, 1237–1256. [Google Scholar] [CrossRef] [PubMed]
  181. Kuber, B.; Fadnavis, M.; Chatterjee, B. Role of Angiotensin Receptor Blockers in the Context of Alzheimer’s Disease. Fundam. Clin. Pharmacol. 2023, 37, 429–445. [Google Scholar] [CrossRef]
  182. Santos, C.R.D.; Grigorova, Y.N.; McDevitt, R.A.; Long, J.M.; Cezayirli, D.; Zernetkina, V.; Wei, W.; Haghkar, M.; Morrell, C.H.; Juhasz, O.; et al. Treatment with Losartan, an AT1 Receptor Blocker, Improves Cognitive and Cardiovascular Function in a Dahl Salt-sensitive Rat Model of Age-associated Vascular Dementia. Alzheimer’s Dement. 2022, 18, e062715. [Google Scholar] [CrossRef]
  183. Hajjar, I.; Okafor, M.; Wan, L.; Yang, Z.; Nye, J.A.; Bohsali, A.; Shaw, L.M.; Levey, A.I.; Lah, J.J.; Calhoun, V.D.; et al. Safety and Biomarker Effects of Candesartan in Non-Hypertensive Adults with Prodromal Alzheimer’s Disease. Brain Commun. 2022, 4, fcac270. [Google Scholar] [CrossRef]
  184. Gebre, A.K.; Altaye, B.M.; Atey, T.M.; Tuem, K.B.; Berhe, D.F. Targeting Renin–Angiotensin System Against Alzheimer’s Disease. Front. Pharmacol. 2018, 9, 440. [Google Scholar] [CrossRef]
  185. Ababei, D.-C.; Bild, V.; Macadan, I.; Vasincu, A.; Rusu, R.-N.; Blaj, M.; Stanciu, G.D.; Lefter, R.-M.; Bild, W. Therapeutic Implications of Renin-Angiotensin System Modulators in Alzheimer’s Dementia. Pharmaceutics 2023, 15, 2290. [Google Scholar] [CrossRef]
  186. Cosarderelioglu, C.; Nidadavolu, L.S.; George, C.J.; Oh, E.S.; Bennett, D.A.; Walston, J.D.; Abadir, P.M. Brain Renin–Angiotensin System at the Intersect of Physical and Cognitive Frailty. Front. Neurosci. 2020, 14, 586314. [Google Scholar] [CrossRef]
  187. Cueto-Ureña, C.; Ramírez-Expósito, M.J.; Carrera-González, M.P.; Martínez-Martos, J.M. Physiopathology of the Brain Renin-Angiotensin System. Life 2025, 15, 1333. [Google Scholar] [CrossRef]
  188. Wu, H.; Sun, Q.; Yuan, S.; Wang, J.; Li, F.; Gao, H.; Chen, X.; Yang, R.; Xu, J. AT1 Receptors: Their Actions from Hypertension to Cognitive Impairment. Cardiovasc. Toxicol. 2022, 22, 311–325. [Google Scholar] [CrossRef] [PubMed]
  189. Bloem, B.R.; Okun, M.S.; Klein, C. Parkinson’s Disease. Lancet 2021, 397, 2284–2303. [Google Scholar] [CrossRef]
  190. Contaldi, E.; Magistrelli, L.; Milner, A.; Cosentino, M.; Marino, F.; Comi, C. Potential Protective Role of ACE-Inhibitors and AT1 Receptor Blockers against Levodopa-Induced Dyskinesias: A Retrospective Case-Control Study. Neural Regen. Res. 2021, 16, 2475. [Google Scholar] [CrossRef]
  191. Perez-Lloret, S.; Otero-Losada, M.; Toblli, J.E.; Capani, F. Renin-Angiotensin System as a Potential Target for New Therapeutic Approaches in Parkinson’s Disease. Expert Opin. Investig. Drugs 2017, 26, 1163–1173. [Google Scholar] [CrossRef] [PubMed]
  192. Udovin, L.; Otero-Losada, M.; Bordet, S.; Chevalier, G.; Quarracino, C.; Capani, F.; Pérez-Lloret, S. Effects of Angiotensin Type 1 Receptor Antagonists on Parkinson’s Disease Progression: An Exploratory Study in the PPMI Database. Park. Relat. Disord. 2021, 86, 34–37. [Google Scholar] [CrossRef] [PubMed]
  193. Zhao, H.-R.; Jiang, T.; Tian, Y.-Y.; Gao, Q.; Li, Z.; Pan, Y.; Wu, L.; Lu, J.; Zhang, Y.-D. Angiotensin II Triggers Apoptosis Via Enhancement of NADPH Oxidase-Dependent Oxidative Stress in a Dopaminergic Neuronal Cell Line. Neurochem. Res. 2015, 40, 854–863. [Google Scholar] [CrossRef]
  194. Kobiec, T.; Otero-Losada, M.; Chevalier, G.; Udovin, L.; Bordet, S.; Menéndez-Maissonave, C.; Capani, F.; Pérez-Lloret, S. The Renin–Angiotensin System Modulates Dopaminergic Neurotransmission: A New Player on the Scene. Front. Synaptic Neurosci. 2021, 13, 638519. [Google Scholar] [CrossRef]
  195. Labandeira-Garcia, J.L.; Labandeira, C.M.; Guerra, M.J.; Rodriguez-Perez, A.I. The Role of the Brain Renin-Angiotensin System in Parkinson’s Disease. Transl. Neurodegener. 2024, 13, 22. [Google Scholar] [CrossRef]
  196. Rothlin, R.P.; Pelorosso, F.G.; Duarte, M.; Nicolosi, L.; Ignacio, F.C.; Salgado, M.V.; Vetulli, H. Telmisartan and Losartan: The Marked Differences between Their Chemical and Pharmacological Properties May Explain the Difference in Therapeutic Efficacy in Hospitalized Patients with COVID-19. Pharmacol. Res. Perspect. 2023, 11, e01083. [Google Scholar] [CrossRef] [PubMed]
  197. El-Gendy, M.A.; El-Assal, M.I.A.; Tadros, M.I.; El-Gazayerly, O.N. Olmesartan Medoxomil-Loaded Mixed Micelles: Preparation, Characterization and in-Vitro Evaluation. Future J. Pharm. Sci. 2017, 3, 90–94. [Google Scholar] [CrossRef]
  198. Ahad, A.; Al-Saleh, A.A.; Al-Mohizea, A.M.; Al-Jenoobi, F.I.; Raish, M.; Yassin, A.E.B.; Alam, M.A. Pharmacodynamic Study of Eprosartan Mesylate-Loaded Transfersomes Carbopol® Gel under Dermaroller® on Rats with Methyl Prednisolone Acetate-Induced Hypertension. Biomed. Pharmacother. 2017, 89, 177–184. [Google Scholar] [CrossRef] [PubMed]
  199. Darwish, I.A.; Darwish, H.W.; Bakheit, A.H.; Al-Kahtani, H.M.; Alanazi, Z. Irbesartan (a Comprehensive Profile). In Profiles of Drug Substances, Excipients and Related Methodology; Elsevier: London, UK, 2021; Volume 46, pp. 185–272. ISBN 978-0-12-824127-1. [Google Scholar]
  200. Gebhart, M.; Elvert, C.A.; Schoepf, A.M.; Scheiber, A.; Schwaiger, S.; Karg, C.A.; Gust, R.; Salcher, S. Key Determinants of the Chemo-Sensitizing Activity of Novel Telmisartan Derivatives. Eur. J. Med. Chem. Rep. 2025, 15, 100281. [Google Scholar] [CrossRef]
  201. Anwar, W.; Dawaba, H.; Afouna, M.; Samy, A.; Rashed, M.; Abdelaziz, A. Enhancing the Oral Bioavailability of Candesartan Cilexetil Loaded Nanostructured Lipid Carriers: In Vitro Characterization and Absorption in Rats after Oral Administration. Pharmaceutics 2020, 12, 1047. [Google Scholar] [CrossRef]
  202. Glodzik, L.; Santisteban, M.M. Blood-Brain Barrier Crossing Renin-Angiotensin System Drugs: Considerations for Dementia and Cognitive Decline. Hypertension 2021, 78, 644–646. [Google Scholar] [CrossRef]
  203. Ho, J.K.; Moriarty, F.; Manly, J.J.; Larson, E.B.; Evans, D.A.; Rajan, K.B.; Hudak, E.M.; Hassan, L.; Liu, E.; Sato, N.; et al. Blood-Brain Barrier Crossing Renin-Angiotensin Drugs and Cognition in the Elderly: A Meta-Analysis. Hypertension 2021, 78, 629–643. [Google Scholar] [CrossRef]
  204. Bordet, S.; Grasso, L.; Udovin, L.; Chevalier, G.; Otero-Losada, M.; Capani, F.; Perez-Lloret, S. An Open-Label, Non-randomized, Drug-Repurposing Study to Explore the Clinical Effects of Angiotensin II Type 1 (AT1) Receptor Antagonists on Anxiety and Depression in Parkinson’s Disease. Mov. Disord. Clin. Pract. 2025, 12, 653–658. [Google Scholar] [CrossRef]
  205. Balthazar, L.; Lages, Y.V.M.; Romano, V.C.; Landeira-Fernandez, J.; Krahe, T.E. The Association between the Renin-Angiotensin System and the Hypothalamic-Pituitary-Adrenal Axis in Anxiety Disorders: A Systematic Review of Animal Studies. Psychoneuroendocrinology 2021, 132, 105354. [Google Scholar] [CrossRef]
  206. Raasch, W.; Wittmershaus, C.; Dendorfer, A.; Voges, I.; Pahlke, F.; Dodt, C.; Dominiak, P.; Jöhren, O. Angiotensin II Inhibition Reduces Stress Sensitivity of Hypothalamo-Pituitary-Adrenal Axis in Spontaneously Hypertensive Rats. Endocrinology 2006, 147, 3539–3546. [Google Scholar] [CrossRef] [PubMed]
  207. Armando, I.; Carranza, A.; Nishimura, Y.; Hoe, K.L.; Barontini, M.; Saavedra, J.M. The Role of Angiotensin II AT1 Receptors in the Sympathoadrenal Response to Stress. In Catecholamine Research; Nagatsu, T., Nabeshima, T., McCarty, R., Goldstein, D.S., Eds.; Advances in Behavioral Biology; Springer: Boston, MA, USA, 2002; Volume 53, pp. 313–316. ISBN 978-1-4419-3388-1. [Google Scholar]
  208. Konain, K.; Faheem, M.; Ullah, K.; Ayub, S.; Ahmed, J.; Huma, Z.; Javed, A.; Khan, T.; Hussain, D.; Khan, I.N. Biomarker-Guided Drug Repurposing and Molecular Validation of Angiotensin-2 Receptor Type-1 in Brain Tumor. Precis. Med. Commun. 2023, 3, 27–42. [Google Scholar] [CrossRef]
  209. O’Rawe, M.; Wickremesekera, A.C.; Pandey, R.; Young, D.; Sim, D.; FitzJohn, T.; Burgess, C.; Kaye, A.H.; Tan, S.T. Treatment of Glioblastoma with Re-Purposed Renin-Angiotensin System Modulators: Results of a Phase I Clinical Trial. J. Clin. Neurosci. 2022, 95, 48–54. [Google Scholar] [CrossRef] [PubMed]
  210. Ridgway, H.; Chasapis, C.T.; Kelaidonis, K.; Ligielli, I.; Moore, G.J.; Gadanec, L.K.; Zulli, A.; Apostolopoulos, V.; Mavromoustakos, T.; Matsoukas, J.M. Understanding the Driving Forces That Trigger Mutations in SARS-CoV-2: Mutational Energetics and the Role of Arginine Blockers in COVID-19 Therapy. Viruses 2022, 14, 1029. [Google Scholar] [CrossRef] [PubMed]
  211. Hajji, N.; Garcia-Revilla, J.; Soto, M.S.; Perryman, R.; Symington, J.; Quarles, C.C.; Healey, D.R.; Guo, Y.; Orta-Vázquez, M.L.; Mateos-Cordero, S.; et al. Arginine Deprivation Alters Microglial Polarity and Synergizes with Radiation to Eradicate Non-Arginine-Auxotrophic Glioblastoma Tumors. J. Clin. Investig. 2022, 132, e142137. [Google Scholar] [CrossRef]
  212. Perryman, R.; Renziehausen, A.; Shaye, H.; Kostagianni, A.D.; Tsiailanis, A.D.; Thorne, T.; Chatziathanasiadou, M.V.; Sivolapenko, G.B.; El Mubarak, M.A.; Han, G.W.; et al. Inhibition of the Angiotensin II Type 2 Receptor AT2R Is a Novel Therapeutic Strategy for Glioblastoma. Proc. Natl. Acad. Sci. USA 2022, 119, 1–12. [Google Scholar] [CrossRef]
  213. Juillerat-Jeanneret, L. The Other Angiotensin II Receptor: AT2R as a Therapeutic Target. J. Med. Chem. 2020, 63, 1978–1995. [Google Scholar] [CrossRef]
  214. Arrieta, O.; Pineda-Olvera, B.; Guevara-Salazar, P.; Hernández-Pedro, N.; Morales-Espinosa, D.; Cerón-Lizarraga, T.L.; González-De La Rosa, C.H.; Rembao, D.; Segura-Pacheco, B.; Sotelo, J. Expression of AT1 and AT2 Angiotensin Receptors in Astrocytomas Is Associated with Poor Prognosis. Br. J. Cancer 2008, 99, 160–166. [Google Scholar] [CrossRef]
  215. Li, X.; Wang, X.; Xie, J.; Liang, B.; Wu, J. Suppression of Angiotensin-(1–7) on the Disruption of Blood-Brain Barrier in Rat of Brain Glioma. Pathol. Oncol. Res. 2019, 25, 429–435. [Google Scholar] [CrossRef]
  216. Lin, W.-Y.; Li, L.-H.; Hsiao, Y.-Y.; Wong, W.-T.; Chiu, H.-W.; Hsu, H.-T.; Peng, Y.-J.; Ho, C.-L.; Chernikov, O.V.; Cheng, S.-M.; et al. Repositioning of the Angiotensin II Receptor Antagonist Candesartan as an Anti-Inflammatory Agent With NLRP3 Inflammasome Inhibitory Activity. Front. Immunol. 2022, 13, 870627. [Google Scholar] [CrossRef]
  217. Awad, K.; Zaki, M.M.; Mohammed, M.; Lewek, J.; Lavie, C.J.; Banach, M. Effect of the Renin-Angiotensin System Inhibitors on Inflammatory Markers: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Mayo Clin. Proc. 2022, 97, 1808–1823. [Google Scholar] [CrossRef]
  218. Stegbauer, J.; Lee, D.-H.; Seubert, S.; Ellrichmann, G.; Manzel, A.; Kvakan, H.; Muller, D.N.; Gaupp, S.; Rump, L.C.; Gold, R.; et al. Role of the Renin-Angiotensin System in Autoimmune Inflammation of the Central Nervous System. Proc. Natl. Acad. Sci. USA 2009, 106, 14942–14947. [Google Scholar] [CrossRef] [PubMed]
  219. Haliga, R.E.; Cojocaru, E.; Sîrbu, O.; Hrițcu, I.; Alexa, R.E.; Haliga, I.B.; Șorodoc, V.; Coman, A.E. Immunomodulatory Effects of RAAS Inhibitors: Beyond Hypertension and Heart Failure. Biomedicines 2025, 13, 1779. [Google Scholar] [CrossRef] [PubMed]
  220. Deraos, G.; Chatzantoni, K.; Matsoukas, M.-T.; Tselios, T.; Deraos, S.; Katsara, M.; Papathanasopoulos, P.; Vynios, D.; Apostolopoulos, V.; Mouzaki, A.; et al. Citrullination of Linear and Cyclic Altered Peptide Ligands from Myelin Basic Protein (MBP87−99) Epitope Elicits a Th1 Polarized Response by T Cells Isolated from Multiple Sclerosis Patients: Implications in Triggering Disease. J. Med. Chem. 2008, 51, 7834–7842. [Google Scholar] [CrossRef] [PubMed]
  221. Mantzourani, E.; Mavromoustakos, T.; Platts, J.; Matsoukas, J.; Tselios, T. Structural Requirements for Binding of Myelin Basic Protein (MBP) Peptides to MHC II: Effects on Immune Regulation. Curr. Med. Chem. 2005, 12, 1521–1535. [Google Scholar] [CrossRef]
  222. Ridgway, H.; Moore, G.J.; Mavromoustakos, T.; Tsiodras, S.; Ligielli, I.; Kelaidonis, K.; Chasapis, C.T.; Gadanec, L.K.; Zulli, A.; Apostolopoulos, V.; et al. Discovery of a New Generation of Angiotensin Receptor Blocking Drugs: Receptor Mechanisms and in Silico Binding to Enzymes Relevant to SARS-CoV-2. Comput. Struct. Biotechnol. J. 2022, 20, 2091–2111. [Google Scholar] [CrossRef]
  223. Lara, V.S.; Silva, R.A.D.; Ferrari, T.P.; Santos, C.F.D.; Oliveira, S.H.P.D. Losartan Plays a Fungistatic and Fungicidal Activity Against Candida Albicans Biofilms: Drug Repurposing for Localized Candidosis. ASSAY Drug Dev. Technol. 2023, 21, 157–165. [Google Scholar] [CrossRef]
  224. Sumners, C.; Peluso, A.A.; Haugaard, A.H.; Bertelsen, J.B.; Steckelings, U.M. Anti-fibrotic Mechanisms of Angiotensin AT2-receptor Stimulation. Acta Physiol. 2019, 227, e13280. [Google Scholar] [CrossRef]
  225. Murphy, A.M.; Wong, A.L.; Bezuhly, M. Modulation of Angiotensin II Signaling in the Prevention of Fibrosis. Fibrogenesis Tissue Repair 2015, 8, 7. [Google Scholar] [CrossRef]
  226. Chappell, M.C.; Al Zayadneh, E.M. Angiotensin-(1–7) and the Regulation of Anti-Fibrotic Signaling Pathways. J. Cell Signal 2017, 2, 134. [Google Scholar] [CrossRef]
  227. An, Y.; Xu, C.; Liu, W.; Jiang, J.; Ye, P.; Yang, M.; Zhu, W.; Yu, J.; Yu, M.; Sun, W.; et al. Angiotensin II Type-2 Receptor Attenuates Liver Fibrosis Progression by Suppressing IRE1α-XBP1 Pathway. Cell. Signal. 2024, 113, 110935. [Google Scholar] [CrossRef]
  228. Corey, K.E.; Shah, N.; Misdraji, J.; Abu Dayyeh, B.K.; Zheng, H.; Bhan, A.K.; Chung, R.T. The Effect of Angiotensin-blocking Agents on Liver Fibrosis in Patients with Hepatitis C. Liver Int. 2009, 29, 748–753. [Google Scholar] [CrossRef]
  229. Kawaguchi, Y.; Takagi, K.; Hara, M.; Fukasawa, C.; Sugiura, T.; Nishimagi, E.; Harigai, M.; Kamatani, N. Angiotensin II in the Lesional Skin of Systemic Sclerosis Patients Contributes to Tissue Fibrosis via Angiotensin II Type 1 Receptors. Arthritis Rheum. 2004, 50, 216–226. [Google Scholar] [CrossRef] [PubMed]
  230. Dziadzio, M.; Denton, C.P.; Smith, R.; Howell, K.; Blann, A.; Bowers, E.; Black, C.M. Losartan Therapy for Raynaud’s Phenomenon and Scleroderma: Clinical and Biochemical Findings in a Fifteen-Week, Randomized, Parallel-Group, Controlled Trial. Arthritis Rheum. 1999, 42, 2646–2655. [Google Scholar] [CrossRef] [PubMed]
  231. Iwane, S.; Nemoto, W.; Miyamoto, T.; Hayashi, T.; Tanaka, M.; Uchitani, K.; Muranaka, T.; Fujitani, M.; Koizumi, Y.; Hirata, A.; et al. Clinical and Preclinical Evidence That Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Prevent Diabetic Peripheral Neuropathy. Sci. Rep. 2024, 14, 1039. [Google Scholar] [CrossRef] [PubMed]
  232. Ogata, Y.; Nemoto, W.; Nakagawasai, O.; Yamagata, R.; Tadano, T.; Tan-No, K. Involvement of Spinal Angiotensin II System in Streptozotocin-Induced Diabetic Neuropathic Pain in Mice. Mol. Pharmacol. 2016, 90, 205–213. [Google Scholar] [CrossRef]
  233. Maxfield, E.K.; Cameron, N.E.; Cotter, M.A.; Dines, K.C. Angiotensin II Receptor Blockade Improves Nerve Function, Modulates Nerve Blood Flow and Stimulates Endoneurial Angiogenesis in Streptozotocin-Diabetic Ratsand Nerve Function. Diabetologia 1993, 36, 1230–1237. [Google Scholar] [CrossRef]
  234. Dikalov, S.I.; Nazarewicz, R.R. Angiotensin II-Induced Production of Mitochondrial Reactive Oxygen Species: Potential Mechanisms and Relevance for Cardiovascular Disease. Antioxid. Redox Signal. 2013, 19, 1085–1094. [Google Scholar] [CrossRef]
  235. Salmenkari, H.; Korpela, R.; Vapaatalo, H. Renin–Angiotensin System in Intestinal Inflammation—Angiotensin Inhibitors to Treat Inflammatory Bowel Diseases? Basic Clin. Pharmacol. Toxicol. 2021, 129, 161–172. [Google Scholar] [CrossRef]
  236. He, L.; Du, J.; Chen, Y.; Liu, C.; Zhou, M.; Adhikari, S.; Rubin, D.T.; Pekow, J.; Li, Y.C. Renin-Angiotensin System Promotes Colonic Inflammation by Inducing TH17 Activation via JAK2/STAT Pathway. Am. J. Physiol. Gastrointest. Liver Physiol. 2019, 316, G774–G784. [Google Scholar] [CrossRef]
  237. Khajah, M.A.; Fateel, M.M.; Ananthalakshmi, K.V.; Luqmani, Y.A. Anti-Inflammatory Action of Angiotensin 1–7 in Experimental Colitis. PLoS ONE 2016, 11, e0150861. [Google Scholar] [CrossRef] [PubMed]
  238. Jacobs, J.D.; Wagner, T.; Gulotta, G.; Liao, C.; Li, Y.C.; Bissonnette, M.; Pekow, J. Impact of Angiotensin II Signaling Blockade on Clinical Outcomes in Patients with Inflammatory Bowel Disease. Dig. Dis. Sci. 2019, 64, 1938–1944. [Google Scholar] [CrossRef] [PubMed]
  239. Pitcher, A.; Spata, E.; Emberson, J.; Davies, K.; Halls, H.; Holland, L.; Wilson, K.; Reith, C.; Child, A.H.; Clayton, T.; et al. Angiotensin Receptor Blockers and β Blockers in Marfan Syndrome: An Individual Patient Data Meta-Analysis of Randomised Trials. Lancet 2022, 400, 822–831. [Google Scholar] [CrossRef] [PubMed]
  240. Habashi, J.P.; Judge, D.P.; Holm, T.M.; Cohn, R.D.; Loeys, B.L.; Cooper, T.K.; Myers, L.; Klein, E.C.; Liu, G.; Calvi, C.; et al. Losartan, an AT1 Antagonist, Prevents Aortic Aneurysm in a Mouse Model of Marfan Syndrome. Science 2006, 312, 117–121. [Google Scholar] [CrossRef]
  241. Habashi, J.P.; Doyle, J.J.; Holm, T.M.; Aziz, H.; Schoenhoff, F.; Bedja, D.; Chen, Y.; Modiri, A.N.; Judge, D.P.; Dietz, H.C. Angiotensin II Type 2 Receptor Signaling Attenuates Aortic Aneurysm in Mice Through ERK Antagonism. Science 2011, 332, 361–365. [Google Scholar] [CrossRef]
  242. Cohn, R.D.; Van Erp, C.; Habashi, J.P.; Soleimani, A.A.; Klein, E.C.; Lisi, M.T.; Gamradt, M.; Ap Rhys, C.M.; Holm, T.M.; Loeys, B.L.; et al. Angiotensin II Type 1 Receptor Blockade Attenuates TGF-β–Induced Failure of Muscle Regeneration in Multiple Myopathic States. Nat. Med. 2007, 13, 204–210. [Google Scholar] [CrossRef]
  243. Asano, K.; Cantalupo, A.; Sedes, L.; Ramirez, F. Pathophysiology and Therapeutics of Thoracic Aortic Aneurysm in Marfan Syndrome. Biomolecules 2022, 12, 128. [Google Scholar] [CrossRef]
  244. Matsoukas, J.; Apostolopoulos, V.; Zulli, A.; Moore, G.; Kelaidonis, K.; Moschovou, K.; Mavromoustakos, T. From Angiotensin II to Cyclic Peptides and Angiotensin Receptor Blockers (ARBs): Perspectives of ARBs in COVID-19 Therapy. Molecules 2021, 26, 618. [Google Scholar] [CrossRef]
  245. Jardine, M.J.; Kotwal, S.S.; Bassi, A.; Hockham, C.; Jones, M.; Wilcox, A.; Pollock, C.; Burrell, L.M.; McGree, J.; Rathore, V.; et al. Angiotensin Receptor Blockers for the Treatment of COVID-19: Pragmatic, Adaptive, Multicentre, Phase 3, Randomised Controlled Trial. BMJ 2022, 379, e072175. [Google Scholar] [CrossRef]
  246. Martins, A.L.V.; Annoni, F.; Da Silva, F.A.; Bolais-Ramos, L.; De Oliveira, G.C.; Ribeiro, R.C.; Diniz, M.M.L.; Silva, T.G.F.; Pinheiro, B.D.; Rodrigues, N.A.; et al. Angiotensin-(1–7) Infusion in COVID-19 Patients Admitted to the ICU: A Seamless Phase 1–2 Randomized Clinical Trial. Ann. Intensive Care 2024, 14, 139. [Google Scholar] [CrossRef]
  247. Moreira, F.R.C.; De Oliveira, T.A.; Ramos, N.E.; Abreu, M.A.D.; Simões E Silva, A.C. The Role of Renin Angiotensin System in the Pathophysiology of Rheumatoid Arthritis. Mol. Biol. Rep. 2021, 48, 6619–6629. [Google Scholar] [CrossRef]
  248. Kaur, B.; Singh, H.; Choudhary, G.; Prakash, A.; Medhi, B.; Chatterjee, D.; Saini, U.C.; Kaur, J.; Verma, I.; Sharma, S. Natural Angiotensin II Type 1 Receptor Inhibitors: Virtual Screening and in Vitro Evaluation of Beta-1,2,3,4,6-Penta-O-Galloyl-d-Glucopyranose, Icarrin, and Sesamin for Osteoarthritis Therapy. Int. J. Biol. Macromol. 2025, 309, 142184. [Google Scholar] [CrossRef]
  249. Guo, Z.; Di, J.; Zhang, Z.; Chen, S.; Mao, X.; Wang, Z.; Yan, Z.; Li, X.; Tian, Z.; Mu, C.; et al. Antihypertensive Drug-Associated Adverse Events in Osteoarthritis: A Study of a Large Real-World Sample Based on the FAERS Database. Front. Pharmacol. 2024, 15, 1404427. [Google Scholar] [CrossRef]
  250. Substance Abuse and Mental Health Services Administration. Key Substance Use and Mental Health Indicators in the United States: Results from the 2019 National Survey on Drug Use and Health; Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services: Rockville, MD, USA, 2020. [Google Scholar]
  251. Ignaszewski, M.J. The Epidemiology of Drug Abuse. J. Clin. Pharmacol. 2021, 61, S10–S17. [Google Scholar] [CrossRef]
  252. Ridgway, H.; Moore, G.J.; Gadanec, L.K.; Matsoukas, J.M. Docking Simulations of G-Protein Coupled Receptors Uncover Crossover Binding Patterns of Diverse Ligands to Angiotensin, Alpha-Adrenergic and Opioid Receptors: Implications for Cardiovascular Disease and Addiction. Biomolecules 2025, 15, 855. [Google Scholar] [CrossRef]
  253. Colombo, G.L.; Caruggi, M.; Ottolini, C.; Maggioni, A.P. Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) and Resource Utilization and Costs in Italy. Vasc. Health Risk Manag. 2008, 4, 223–234. [Google Scholar] [CrossRef] [PubMed]
  254. Latini, R.; Masson, S.; Anand, I.; Judd, D.; Maggioni, A.P.; Chiang, Y.-T.; Bevilacqua, M.; Salio, M.; Cardano, P.; Dunselman, P.H.J.M.; et al. Effects of Valsartan on Circulating Brain Natriuretic Peptide and Norepinephrine in Symptomatic Chronic Heart Failure: The Valsartan Heart Failure Trial (Val-HeFT). Circulation 2002, 106, 2454–2458. [Google Scholar] [CrossRef]
  255. Sharma, M. The RENAAL Study Investigation. Clin. Diabetes 2002, 20, 19–20. [Google Scholar] [CrossRef]
  256. Lewis, E.J.; Hunsicker, L.G.; Clarke, W.R.; Berl, T.; Pohl, M.A.; Lewis, J.B.; Ritz, E.; Atkins, R.C.; Rohde, R.; Raz, I. Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes. N. Engl. J. Med. 2001, 345, 851–860. [Google Scholar] [CrossRef] [PubMed]
  257. The ONTARGET Investigators. Telmisartan, Ramipril, or Both in Patients at High Risk for Vascular Events. N. Engl. J. Med. 2008, 358, 1547–1559. [Google Scholar] [CrossRef]
  258. Pfeffer, M.A.; McMurray, J.J.V.; Velazquez, E.J.; Rouleau, J.-L.; Køber, L.; Maggioni, A.P.; Solomon, S.D.; Swedberg, K.; Van De Werf, F.; White, H.; et al. Valsartan, Captopril, or Both in Myocardial Infarction Complicated by Heart Failure, Left Ventricular Dysfunction, or Both. N. Engl. J. Med. 2003, 349, 1893–1906. [Google Scholar] [CrossRef]
  259. Dickstein, K.; Kjekshus, J. Effects of Losartan and Captopril on Mortality and Morbidity in High-Risk Patients after Acute Myocardial Infarction: The OPTIMAAL Randomised Trial. Lancet 2002, 360, 752–760. [Google Scholar] [CrossRef]
  260. Suzuki, H.; Kusuyama, T.; Omori, Y.; Soda, T.; Tsunoda, F.; Sato, T.; Shoji, M.; Iso, Y.; Kondo, T.; Koba, S.; et al. Inhibitory Effect of Candesartan Cilexetil on Left Ventricular Remodeling After Myocardial Infarction. Int. Heart J. 2006, 47, 715–725. [Google Scholar] [CrossRef]
  261. Akshayraj Vanrajbhai, C.; Thorat, V.M.; Patel, V.S.; Patil, K.P.; Chawla, L.L. Evaluation of Anxiolytic Activity of Angiotensin Receptor Blockers Using Actophotometer Test in Wistar Rats. Cureus 2024, 16, e69798. [Google Scholar] [CrossRef] [PubMed]
  262. Datta, M.; Chatterjee, S.; Perez, E.M.; Gritsch, S.; Roberge, S.; Duquette, M.; Chen, I.X.; Naxerova, K.; Kumar, A.S.; Ghosh, M.; et al. Losartan Controls Immune Checkpoint Blocker-Induced Edema and Improves Survival in Glioblastoma Mouse Models. Proc. Natl. Acad. Sci. USA 2023, 120, 1–11. [Google Scholar] [CrossRef] [PubMed]
  263. Abbas, H.A.; Gad, A.I.; El-Sayed, M.A.; El-Ganiny, A.M. Impeding Virulence of Candida Albicans by Candesartan and Domperidone. Curr. Microbiol. 2021, 78, 3957–3967. [Google Scholar] [CrossRef] [PubMed]
  264. Couluris, M.; Kinder, B.W.; Xu, P.; Gross-King, M.; Krischer, J.; Panos, R.J. Treatment of Idiopathic Pulmonary Fibrosis with Losartan: A Pilot Project. Lung 2012, 190, 523–527. [Google Scholar] [CrossRef]
  265. Attia, Y.M.; Elalkamy, E.F.; Hammam, O.A.; Mahmoud, S.S.; El-Khatib, A.S. Telmisartan, an AT1 Receptor Blocker and a PPAR Gamma Activator, Alleviates Liver Fibrosis Induced Experimentally by Schistosoma Mansoni Infection. Parasit. Vectors 2013, 6, 199. [Google Scholar] [CrossRef]
  266. Mostafa, T.M.; El-Azab, G.A.; Badra, G.A.; Abdelwahed, A.S.; Elsayed, A.A. Effect of Candesartan and Ramipril on Liver Fibrosis in Patients with Chronic Hepatitis C Viral Infection: A Randomized Controlled Prospective Study. Curr. Ther. Res. Clin. Exp. 2021, 95, 100654. [Google Scholar] [CrossRef]
  267. Liu, R.; Wang, Q.; Ding, Z.; Zhang, X.; Li, Y.; Zang, Y.; Zhang, G. Silibinin Augments the Antifibrotic Effect of Valsartan Through Inactivation of TGF-Β1 Signaling in Kidney. Drug Des. Devel Ther. 2020, 14, 603–611. [Google Scholar] [CrossRef]
  268. Cavusoglu, T.; Karadeniz, T.; Cagiltay, E.; Karadeniz, M.; Yigitturk, G.; Acikgoz, E.; Uyanikgil, Y.; Ates, U.; Tuglu, M.; Erbas, O. The Protective Effect of Losartan on Diabetic Neuropathy in a Diabetic Rat Model. Exp. Clin. Endocrinol. Diabetes 2015, 123, 479–484. [Google Scholar] [CrossRef]
  269. Al-Rejaie, S.S.; Abuohashish, H.M.; Ahmed, M.M.; Arrejaie, A.S.; Aleisa, A.M.; AlSharari, S.D. Telmisartan Inhibits Hyperalgesia and Inflammatory Progression in a Diabetic Neuropathic Pain Model of Wistar Rats. Neurosciences 2015, 20, 115–123. [Google Scholar] [CrossRef]
  270. Wengrower, D.; Zanninelli, G.; Latella, G.; Necozione, S.; Metanes, I.; Israeli, E.; Lysy, J.; Pines, M.; Papo, O.; Goldin, E. Losartan Reduces Trinitrobenzene Sulphonic Acid-Induced Colorectal Fibrosis in Rats. Can. J. Gastroenterol. 2012, 26, 33–39. [Google Scholar] [CrossRef]
  271. Arab, H.H.; Al-Shorbagy, M.Y.; Abdallah, D.M.; Nassar, N.N. Telmisartan Attenuates Colon Inflammation, Oxidative Perturbations and Apoptosis in a Rat Model of Experimental Inflammatory Bowel Disease. PLoS ONE 2014, 9, e97193. [Google Scholar] [CrossRef] [PubMed]
  272. Okawada, M.; Miyasaka, E.A.; Teitelbaum, D.H. Blockade of Angiotensin II Type 1a Receptor in a DSS Model of Colitis Results in Significant Expansion of Foxp3 Regulatory T Cells. J. Am. Coll. Surg. 2010, 211, S12. [Google Scholar] [CrossRef]
  273. Santiago, O.I.; Rivera, E.; Ferder, L.; Appleyard, C.B. An Angiotensin II Receptor Antagonist Reduces Inflammatory Parameters in Two Models of Colitis. Regul. Pept. 2008, 146, 250–259. [Google Scholar] [CrossRef] [PubMed]
  274. Groenink, M.; Den Hartog, A.W.; Franken, R.; Radonic, T.; De Waard, V.; Timmermans, J.; Scholte, A.J.; Van Den Berg, M.P.; Spijkerboer, A.M.; Marquering, H.A.; et al. Losartan Reduces Aortic Dilatation Rate in Adults with Marfan Syndrome: A Randomized Controlled Trial. Eur. Heart J. 2013, 34, 3491–3500. [Google Scholar] [CrossRef]
  275. Muiño-Mosquera, L.; De Backer, J. Angiotensin-II Receptor Blockade in Marfan Syndrome. Lancet 2019, 394, 2206–2207. [Google Scholar] [CrossRef]
  276. Takagi, H.; Yamamoto, H.; Iwata, K.; Goto, S.; Umemoto, T. An Evidence-Based Hypothesis for Beneficial Effects of Telmisartan on Marfan Syndrome. Int. J. Cardiol. 2012, 158, 101–102. [Google Scholar] [CrossRef]
  277. Duarte, M.; Pelorosso, F.; Nicolosi, L.N.; Victoria Salgado, M.; Vetulli, H.; Aquieri, A.; Azzato, F.; Castro, M.; Coyle, J.; Davolos, I.; et al. Telmisartan for Treatment of COVID-19 Patients: An Open Multicenter Randomized Clinical Trial. eClinicalMedicine 2021, 37, 100962. [Google Scholar] [CrossRef]
  278. Pedrosa, M.A.; Valenzuela, R.; Garrido-Gil, P.; Labandeira, C.M.; Navarro, G.; Franco, R.; Labandeira-Garcia, J.L.; Rodriguez-Perez, A.I. Experimental Data Using Candesartan and Captopril Indicate No Double-Edged Sword Effect in COVID-19. Clin. Sci. 2021, 135, 465–481. [Google Scholar] [CrossRef] [PubMed]
  279. Wang, X.; Chen, X.; Huang, W.; Zhang, P.; Guo, Y.; Körner, H.; Wu, H.; Wei, W. Losartan Suppresses the Inflammatory Response in Collagen-Induced Arthritis by Inhibiting the MAPK and NF-κB Pathways in B and T Cells. Inflammopharmacol 2019, 27, 487–502. [Google Scholar] [CrossRef] [PubMed]
  280. Sagawa, K.; Nagatani, K.; Komagata, Y.; Yamamoto, K. Angiotensin Receptor Blockers Suppress Antigen-specific T Cell Responses and Ameliorate Collagen-induced Arthritis in Mice. Arthritis Rheum. 2005, 52, 1920–1928. [Google Scholar] [CrossRef]
  281. Deng, Z.; Chen, F.; Liu, Y.; Wang, J.; Lu, W.; Jiang, W.; Zhu, W. Losartan Protects against Osteoarthritis by Repressing the TGF-Β1 Signaling Pathway via Upregulation of PPARγ. J. Orthop. Transl. 2021, 29, 30–41. [Google Scholar] [CrossRef] [PubMed]
  282. Karádi, D.Á.; Galambos, A.R.; Lakatos, P.P.; Apenberg, J.; Abbood, S.K.; Balogh, M.; Király, K.; Riba, P.; Essmat, N.; Szűcs, E.; et al. Telmisartan Is a Promising Agent for Managing Neuropathic Pain and Delaying Opioid Analgesic Tolerance in Rats. Int. J. Mol. Sci. 2023, 24, 7970. [Google Scholar] [CrossRef]
  283. Zhao, W.; Shen, F.; Yao, J.; Su, S.; Zhao, Z. Angiotensin II Receptor Type 1 Blocker Candesartan Improves Morphine Tolerance by Reducing Morphine-induced Inflammatory Response and Cellular Activation of BV2 Cells via the PPARγ/AMPK Signaling Pathway. Mol. Med. Rep. 2022, 26, 318. [Google Scholar] [CrossRef]
  284. Moutevelis-Minakakis, P.; Gianni, M.; Stougiannou, H.; Zoumpoulakis, P.; Zoga, A.; Vlahakos, A.D.; Iliodromitis, E.; Mavromoustakos, T. Design and Synthesis of Novel Antihypertensive Drugs. Bioorganic Med. Chem. Lett. 2003, 13, 1737–1740. [Google Scholar] [CrossRef]
  285. Mavromoustakos, T.; Moutevelis-Minakakis, P.; Kokotos, C.G.; Kontogianni, P.; Politi, A.; Zoumpoulakis, P.; Findlay, J.; Cox, A.; Balmforth, A.; Zoga, A.; et al. Synthesis, Binding Studies and in Vivo Biological Evaluation of Novel Non-Peptide Antihypertensive Analogues. Bioorganic Med. Chem. 2006, 14, 4353–4360. [Google Scholar] [CrossRef]
  286. Zoumpoulakis, P.; Politi, A.; Grdadolnik, S.G.; Matsoukas, J.; Mavromoustakos, T. Structure Elucidation and Conformational Study of V8. J. Pharm. Biomed. Anal. 2006, 40, 1097–1104. [Google Scholar] [CrossRef]
  287. Agelis, G.; Roumelioti, P.; Resvani, A.; Durdagi, S.; Androutsou, M.-E.; Kelaidonis, K.; Vlahakos, D.; Mavromoustakos, T.; Matsoukas, J. An Efficient Synthesis of a Rationally Designed 1,5 Disubstituted Imidazole AT1 Angiotensin II Receptor Antagonist: Reorientation of Imidazole Pharmacophore Groups in Losartan Reserves High Receptor Affinity and Confirms Docking Studies. J. Comput. Aided Mol. Des. 2010, 24, 749–758. [Google Scholar] [CrossRef]
  288. Agelis, G.; Resvani, A.; Durdagi, S.; Spyridaki, K.; Tůmová, T.; Slaninová, J.; Giannopoulos, P.; Vlahakos, D.; Liapakis, G.; Mavromoustakos, T.; et al. The Discovery of New Potent Non-Peptide Angiotensin II AT1 Receptor Blockers: A Concise Synthesis, Molecular Docking Studies and Biological Evaluation of N-Substituted 5-Butylimidazole Derivatives. Eur. J. Med. Chem. 2012, 55, 358–374. [Google Scholar] [CrossRef]
  289. Agelis, G.; Resvani, A.; Ntountaniotis, D.; Chatzigeorgiou, P.; Koukoulitsa, C.; Androutsou, M.E.; Plotas, P.; Matsoukas, J.; Mavromoustakos, T.; Čendak, T.; et al. Interactions of the Potent Synthetic AT1 Antagonist Analog BV6 with Membrane Bilayers and Mesoporous Silicate Matrices. Biochim. Et. Biophys. Acta (BBA)—Biomembr. 2013, 1828, 1846–1855. [Google Scholar] [CrossRef]
  290. Moore, G.J.; Ridgway, H.; Kelaidonis, K.; Chasapis, C.T.; Ligielli, I.; Mavromoustakos, T.; Bojarska, J.; Matsoukas, J.M. Actions of Novel Angiotensin Receptor Blocking Drugs, Bisartans, Relevant for COVID-19 Therapy: Biased Agonism at Angiotensin Receptors and the Beneficial Effects of Neprilysin in the Renin Angiotensin System. Molecules 2022, 27, 4854. [Google Scholar] [CrossRef] [PubMed]
  291. Kelaidonis, K.; Ligielli, I.; Letsios, S.; Vidali, V.P.; Mavromoustakos, T.; Vassilaki, N.; Moore, G.J.; Hoffmann, W.; Węgrzyn, K.; Ridgway, H.; et al. Computational and Enzymatic Studies of Sartans in SARS-CoV-2 Spike RBD-ACE2 Binding: The Role of Tetrazole and Perspectives as Antihypertensive and COVID-19 Therapeutics. Int. J. Mol. Sci. 2023, 24, 8454. [Google Scholar] [CrossRef] [PubMed]
  292. Agelis, G.; Resvani, A.; Koukoulitsa, C.; Tůmová, T.; Slaninová, J.; Kalavrizioti, D.; Spyridaki, K.; Afantitis, A.; Melagraki, G.; Siafaka, A.; et al. Rational Design, Efficient Syntheses and Biological Evaluation of N, N′-Symmetrically Bis-Substituted Butylimidazole Analogs as a New Class of Potent Angiotensin II Receptor Blockers. Eur. J. Med. Chem. 2013, 62, 352–370. [Google Scholar] [CrossRef] [PubMed]
  293. Tsiailanis, A.D.; Renziehausen, A.; Kiriakidi, S.; Vrettos, E.I.; Markopoulos, G.S.; Sayyad, N.; Hirmiz, B.; Aguilar, M.-I.; Del Borgo, M.P.; Kolettas, E.; et al. Enhancement of Glioblastoma Multiforme Therapy through a Novel Quercetin-Losartan Hybrid. Free Radic. Biol. Med. 2020, 160, 391–402. [Google Scholar] [CrossRef] [PubMed]
  294. Tsiailanis, A.D.; Vrettos, E.I.; Choleva, M.; Kiriakidi, S.; Ganai, A.M.; Patha, T.K.; Karpoormath, R.; Mavromoustakos, T.; Fragopoulou, E.; Tzakos, A.G. Development of a DHA-Losartan Hybrid as a Potent Inhibitor of Multiple Pathway-Induced Platelet Aggregation. J. Biomol. Struct. Dyn. 2022, 40, 13889–13900. [Google Scholar] [CrossRef]
  295. Georgiou, N.; Gkalpinos, V.K.; Katsakos, S.D.; Vassiliou, S.; Tzakos, A.G.; Mavromoustakos, T. Rational Design and Synthesis of AT1R Antagonists. Molecules 2021, 26, 2927. [Google Scholar] [CrossRef]
  296. Kritsi, E.; Matsoukas, M.-T.; Potamitis, C.; Karageorgos, V.; Detsi, A.; Magafa, V.; Liapakis, G.; Mavromoustakos, T.; Zoumpoulakis, P. Exploring New Scaffolds for Angiotensin II Receptor Antagonism. Bioorganic Med. Chem. 2016, 24, 4444–4451. [Google Scholar] [CrossRef]
  297. Inada, Y.; Nakane, T.; Chiba, S. Binding of KRH-594, an Antagonist of the Angiotensin II Type 1 Receptor, to Cloned Human and Rat Angiotensin II Receptors. Fundam. Clin. Pharmacol. 2002, 16, 317–323. [Google Scholar] [CrossRef]
  298. Hirata, T.; Nomiyama, J.; Sakae, N.; Nishimura, K.; Yokomoto, M.; Inoue, S.; Tamura, K.; Okuhira, M.; Amano, H.; Nagao, Y. Acyliminothiadiazoline Derivatives: New, Highly Potent, and Orally Active Angiotensin II Receptor Antagonists. Bioorganic Med. Chem. Lett. 1996, 6, 1469–1474. [Google Scholar] [CrossRef]
  299. Tamura, K.; Okuhira, M.; Amano, H.; Inokuma, K.; Hirata, T.; Mikoshiba, I.; Hashimoto, K. Pharmacologic Profiles of KRH-594, a Novel Nonpeptide Angiotensin II-Receptor Antagonist. J. Cardiovasc. Pharmacol. 1997, 30, 607–615. [Google Scholar] [CrossRef]
  300. Kotobuki, P. (Kotobuki Research Laboratories, Kotobuki Seiyaku Company, Ltd., Kawagoe, Japan). Unpublished Data Held on File.
  301. Patterson, D.; Webster, J.; McInnes, G.; Brady, A.; MacDonald, T. The Effects of KT3-671, a New Angiotensin II (AT 1) Receptor Blocker in Mild to Moderate Hypertension. Br. J. Clin. Pharmacol. 2003, 56, 513–519. [Google Scholar] [CrossRef] [PubMed]
  302. Han, X.-F.; He, X.; Wang, M.; Xu, D.; Hao, L.-P.; Liang, A.-H.; Zhang, J.; Zhou, Z.-M. Discovery of Novel, Potent and Low-Toxicity Angiotensin II Receptor Type 1 (AT1) Blockers: Design, Synthesis and Biological Evaluation of 6-Substituted Aminocarbonyl Benzimidazoles with a Chiral Center. Eur. J. Med. Chem. 2015, 103, 473–487. [Google Scholar] [CrossRef] [PubMed]
  303. Zhu, W.; Bao, X.; Ren, H.; Da, Y.; Wu, D.; Li, F.; Yan, Y.; Wang, L.; Chen, Z. N-Phenyl Indole Derivatives as AT1 Antagonists with Anti-Hypertension Activities: Design, Synthesis and Biological Evaluation. Eur. J. Med. Chem. 2016, 115, 161–178. [Google Scholar] [CrossRef] [PubMed]
  304. Zhu, W.; Bao, X.; Ren, H.; Liao, P.; Zhu, W.; Yan, Y.; Wang, L.; Chen, Z. Design, Synthesis, and Pharmacological Evaluation of 5-Oxo-1,2,4-Oxadiazole Derivatives as AT1 Antagonists with Antihypertension Activities. Clin. Exp. Hypertens. 2016, 38, 435–442. [Google Scholar] [CrossRef]
  305. Qu, Z.; Wang, X.; Zhang, L.; Lian, X.; Wu, Z. Design, Synthesis, and Biological Evaluation of New Oxadiazole Derivatives as Efficient Antihypertension Drugs. Chem. Res. Toxicol. 2025, 38, 145–150. [Google Scholar] [CrossRef]
  306. Tang, B.; Li, H.; Zhong, Z.; Wu, H.; Shen, H.; Hu, J.; Ma, J.; Wu, J.; Wang, Y. Pharmacological Evaluation on Antihypertensive Activity of a Novel AT1 Angiotensin II Receptor Antagonist. Curr. Sci. 2019, 116, 1987. [Google Scholar] [CrossRef]
  307. Zhu, W.; Da, Y.; Wu, D.; Zheng, H.; Zhu, L.; Wang, L.; Yan, Y.; Chen, Z. Design, Synthesis and Biological Evaluation of New 5-Nitro Benzimidazole Derivatives as AT1 Antagonists with Anti-Hypertension Activities. Bioorganic Med. Chem. 2014, 22, 2294–2302. [Google Scholar] [CrossRef]
  308. Ridgway, H.; Apostolopoulos, V.; Moore, G.J.; Gadanec, L.K.; Zulli, A.; Swiderski, J.; Tsiodras, S.; Kelaidonis, K.; Chasapis, C.T.; Matsoukas, J.M. Computational Evidence for Bisartan Arginine Blockers as Next-Generation Pan-Antiviral Therapeutics Targeting SARS-CoV-2, Influenza, and Respiratory Syncytial Viruses. Viruses 2024, 16, 1776. [Google Scholar] [CrossRef]
  309. Ridgway, H.; Ntallis, C.; Chasapis, C.T.; Kelaidonis, K.; Matsoukas, M.-T.; Plotas, P.; Apostolopoulos, V.; Moore, G.; Tsiodras, S.; Paraskevis, D.; et al. Molecular Epidemiology of SARS-CoV-2: The Dominant Role of Arginine in Mutations and Infectivity. Viruses 2023, 15, 309. [Google Scholar] [CrossRef]
  310. Ridgway, H.; Moore, G.J.; Gadanec, L.K.; Zulli, A.; Apostolopoulos, V.; Hoffmann, W.; Węgrzyn, K.; Vassilaki, N.; Mpekoulis, G.; Zouridakis, M.; et al. Novel Benzimidazole Angiotensin Receptor Blockers with Anti-SARS-CoV-2 Activity Equipotent to That of Nirmatrelvir: Computational and Enzymatic Studies. Expert. Opin. Ther. Targets 2024, 28, 437–459. [Google Scholar] [CrossRef]
  311. Matsoukas, J.M.; Panagiotopoulos, D.; Keramida, M.; Mavromoustakos, T.; Yamdagni, R.; Wu, Q.; Moore, G.J.; Saifeddine, M.; Hollenberg, M.D. Synthesis and Contractile Activities of Cyclic Thrombin Receptor-Derived Peptide Analogues with a Phe-Leu-Leu-Arg Motif: Importance of the Phe/Arg Relative Conformation and the Primary Amino Group for Activity. J. Med. Chem. 1996, 39, 3585–3591. [Google Scholar] [CrossRef]
  312. Maragoudakis, M.E.; Kraniti, N.; Giannopoulou, E.; Alexopoulos, K.; Matsoukas, J. Modulation of Angiogenesis and Progelatinase a by Thrombin Receptor Mimetics and Antagonists. Endothelium 2001, 8, 195–206. [Google Scholar] [CrossRef]
  313. Alexopoulos, K.; Fatseas, P.; Melissari, E.; Vlahakos, D.; Roumelioti, P.; Mavromoustakos, T.; Mihailescu, S.; Paredes-Carbajal, M.C.; Mascher, D.; Matsoukas, J. Design and Synthesis of Novel Biologically Active Thrombin Receptor Non-Peptide Mimetics Based on the Pharmacophoric Cluster Phe/Arg/NH2 of the Ser42-Phe-Leu-Leu-Arg46 Motif Sequence: Platelet Aggregation and Relaxant Activities. J. Med. Chem. 2004, 47, 3338–3352. [Google Scholar] [CrossRef]
  314. Polevaya, L.; Mavromoustakos, T.; Zoumboulakis, P.; Grdadolnik, S.G.; Roumelioti, P.; Giatas, N.; Mutule, I.; Keivish, T.; Vlahakos, D.V.; Iliodromitis, E.K.; et al. Synthesis and Study of a Cyclic Angiotensin II Antagonist Analogue Reveals the Role of Π*–Π* Interactions in the C-Terminal Aromatic Residue for Agonist Activity and Its Structure Resemblance with AT1 Non-Peptide Antagonists. Bioorganic Med. Chem. 2001, 9, 1639–1647. [Google Scholar] [CrossRef]
  315. Yuan, Y.; Li, M.; Apostolopoulos, V.; Matsoukas, J.; Wolf, W.M.; Blaskovich, M.A.T.; Bojarska, J.; Ziora, Z.M. Tetrazoles: A Multi-Potent Motif in Drug Design. Eur. J. Med. Chem. 2024, 279, 116870. [Google Scholar] [CrossRef] [PubMed]
Figure 1. A graphical representation summarizing the topics that will be analyzed in this review article. Specifically, we will start by listing methodologies in which drug repurposing can be achieved (computationally and experimentally). Then, we will examine how drugs that act as AT1 receptor inhibitors can also exert their effects in other pathologies. Specifically, we will start with the ‘core’ diseases that often coexist in patients taking these drugs (HT; hypertension, HF; heart failure, CKD; chronic kidney disease, ACS; acute coronary syndrome). Then, we will list the diseases in which the RAAS plays an important role and therefore inhibition of AT1 receptors could help in the treatment of patients as indicated in research (AD; Alzheimer’s disease, PD; Parkinson’s disease, RA; rheumatoid arthritis, OA; osteoarthritis, DN; diabetic nephropathy, DPN; diabetic peripheral neuropathy, SARS-CoV-2, CS; candidosis, FS; fibrosis, TFSSc; tissue fibrosis in systemic sclerosis, GC; glioma cancer, MS; Marfan syndrome, IBDs; inflammatory bowel diseases, AT; anxiety, PI; pathogenic inflammation, OPA; opioid addiction). Finally, we highlight the work of our laboratory and collaborators towards the design, synthesis, and pharmacological evaluation of innovative bioactive compounds, some of which are also multifunctional drugs, for the treatment of hypertension and other diseases. Such compounds include simple molecules, hybrid molecules, sartan derivatives, and compounds derived from cheminformatic databases.
Figure 1. A graphical representation summarizing the topics that will be analyzed in this review article. Specifically, we will start by listing methodologies in which drug repurposing can be achieved (computationally and experimentally). Then, we will examine how drugs that act as AT1 receptor inhibitors can also exert their effects in other pathologies. Specifically, we will start with the ‘core’ diseases that often coexist in patients taking these drugs (HT; hypertension, HF; heart failure, CKD; chronic kidney disease, ACS; acute coronary syndrome). Then, we will list the diseases in which the RAAS plays an important role and therefore inhibition of AT1 receptors could help in the treatment of patients as indicated in research (AD; Alzheimer’s disease, PD; Parkinson’s disease, RA; rheumatoid arthritis, OA; osteoarthritis, DN; diabetic nephropathy, DPN; diabetic peripheral neuropathy, SARS-CoV-2, CS; candidosis, FS; fibrosis, TFSSc; tissue fibrosis in systemic sclerosis, GC; glioma cancer, MS; Marfan syndrome, IBDs; inflammatory bowel diseases, AT; anxiety, PI; pathogenic inflammation, OPA; opioid addiction). Finally, we highlight the work of our laboratory and collaborators towards the design, synthesis, and pharmacological evaluation of innovative bioactive compounds, some of which are also multifunctional drugs, for the treatment of hypertension and other diseases. Such compounds include simple molecules, hybrid molecules, sartan derivatives, and compounds derived from cheminformatic databases.
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Figure 2. A schematic representation of the compounds designed, synthesized, and studied in silico, in vitro, and in vivo by our laboratory and collaborators over the years. All of them can be separated into 4 major groups: (1) molecules discovered and designed with the contribution of databases, (2) molecules that are sartan derivatives, (3) hybrid molecules, and (4) molecules with a simple structure that satisfactorily inhibit AT1 receptors.
Figure 2. A schematic representation of the compounds designed, synthesized, and studied in silico, in vitro, and in vivo by our laboratory and collaborators over the years. All of them can be separated into 4 major groups: (1) molecules discovered and designed with the contribution of databases, (2) molecules that are sartan derivatives, (3) hybrid molecules, and (4) molecules with a simple structure that satisfactorily inhibit AT1 receptors.
Ijms 26 08819 g002
Table 1. Representative successful stories of drug repurposing. The disease area, drug name, the drug’s original indication and the new (repositioned) indications, as well as their status, can be seen in the table.
Table 1. Representative successful stories of drug repurposing. The disease area, drug name, the drug’s original indication and the new (repositioned) indications, as well as their status, can be seen in the table.
Disease AreaDrug Name/Active IngredientsOriginal IndicationNew Indication(s)New Indication(s) Status
DepressionDuloxetine hydrochlorideMajor Depressive Disorder (MDD) [28,29]Neuropathic pain [30], generalized
anxiety disorder (GAD) [31], osteoarthritis [32],
and stress incontinence [33]
Approved
Fluoxetine hydrochlorideMajor Depressive Disorder (MDD) [34]Premenstrual dysphoric disorder
(PMDD) [35]
Approved
NeurologyAtomoxetine hydrochlorideParkinson’s disease (PD) [36]Attention-deficit hyperactivity
disorder (ADHD) [37]
Approved
BromocriptineParkinson’s disease [38]Diabetes mellitus [39], prolactinomas, and other pituitary adenomas [40]Approved
ChlorpromazineSchizophrenia, bipolar disorder, and acute psychosis [41]Breast cancer [42]Investigational
LithiumDepression, bipolar disorder [43]Cancer [44]Investigational
PenfluridolChronic schizophrenia, acute psychosis, and Tourette syndrome [45]Cancer [46]Investigational
Ropinirole hydrochlorideHypertension (HTN) [47]Parkinson’s disease (PD) [48]Approved
Non-neurologyAspirinAnalgesic,
Antipyretic [49]
Antiplatelet [49], anti-thrombosis [50]Approved
CelecoxibPain,
inflammation, arthritis [51]
Familial adenomatous polyposis [52]Approved
FinasterideBenign prostatic hyperplasia
(BPH) [53]
Hair loss [54]Approved
LosartanHypertension [55]Dystrophic epidermolysis bullosa (RDEB) [56] and COVID-19 [57]Investigational
MinoxidilHypertension (HTN) [58]Hair loss [59]Approved
RaltegravirHIV-1 integrase
Inhibitor [60]
Colorectal cancer [61]Investigational
SildenafilAngina [26]Erectile dysfunction (ED) and
pulmonary arterial hypertension
(PAH) [26]
Approved
ZidovudineFailed clinical trials for cancer [62]Human immunodeficiency virus
(HIV) [62,63]
Approved
CancerAuranofinRheumatoid arthritis (RA) [64]Gastrointestinal stromal tumor
(GIST) [65]
Investigational
CrizotinibClinical trials for anaplastic large
cell lymphoma (ALCL) [66]
Non-small cell lung cancer
(NSCLC) [67]
Approved
ImatinibChronic myeloid leukemia (CML) [68]Gastrointestinal stromal tumors
(GIST) [69]
Approved
Irinotecan hydrochlorideColorectal cancer [70]Pancreatic cancer [71]Approved
Metformin hydrochlorideType 2 diabetes (T2DM) [72]Pancreatic cancer,
endometrial cancer, colorectal
cancer, and esophageal cancer [73,74,75,76]
Investigational
NelfinavirHuman immunodeficiency virus
1 (HIV-1) [77]
Colorectal cancer, lung cancer,
cervical cancer, pancreatic cancer,
ovarian cancer, metastatic
cancer [78]
Investigational
RaloxifeneOsteoporosis [79]Breast cancer [80]Approved
RituximabVarious
cancers [81]
Rheumatoid
arthritis [82]
Approved
SunitinibRenal cell carcinoma (RCC) [83] and
Gastrointestinal stromal tumor
(GIST) [84]
Pancreatic neuroendocrine
tumors (PNETs) [85]
Approved
TrastuzumabHuman epidermal growth factor
receptor 2 (HER2)-positive
breast cancer [86]
Metastatic breast cancer, gastric
cancer, and early breast cancer [87,88,89]
Approved
TemsirolimusRenal cell carcinoma [90]Lung Adenocarcinoma [91]Investigational
InfectiousApmphotericin BAntifungal [92]Leishmaniasis [93], Mucormycosis [94]Approved
DapoxetinePremature ejaculation [95]Zika virus infection [96]Investigational
EverolimusImmunosuppressant [97]Pancreatic neuroendocrine
tumors (PNETs) [98], renal cell carcinoma
(RCC) [99], and subependymal
giant cell astrocytoma
(SEGA) [100]
Approved
FavipiravirInfluenza [101]SARS-CoV-2 [102]Investigational
IvermectinAntiretroviral [103]SARS-CoV-2 [104]Investigational
KetoconazoleFungal infections [105]Cushing’s syndrome [106]Approved
RemdesivirAntiviral [107]SARS-CoV-2 [107]Approved
SirolimusOrgan rejection in patients receiving
renal transplants [108]
Malaria [109]Investigational
ThalidomideMorning sickness (withdrawn) [67]Erythema nodosum leprosum
(Leprosy) [110] and Multiple Myeloma [111]
Approved
Rare and orphanAlefaceptChronic plaque psoriasis [112]Memory T cell-mediated autoimmune diseases, organ transplantation and type I diabetes (T1D) [113]Investigational
BaclofenMuscle relaxant [114]Alcohol use disorder [115]Approved
ClobetasolPsoriasis [116]post-cataract surgery pain and inflammation [117]Approved
Dimethyl fumarateMultiple sclerosis [118]Psoriasis [119], anti-inflammatory [120]Approved
ErythropoietinAnemia [121]Traumatic brain injury [122]Investigational
Ethinyl estradiolTurner syndrome [123]Contraceptive applications [124], acne, hirsutism [125] Approved
FingolimodMultiple sclerosis
(MS) [126]
Alzheimer’s disease [127], cancer [128], diabetic retinopathy [129]Investigational
LiraglutideDiabetes [130]Alzheimer’s disease (AD) [131]Investigational
N-acetyl cysteineMucolytic agent [132]Obsessive–compulsive disorder [133]Investigational
PregabalinNeuropathic pain [134]Generalized anxiety disorder [135]Approved
SimvastatinCardiovascular diseases [136]Anti-tumor agents [137], neurodegenerative disorders [138], preterm labor [139] and Klebsiella pneumoniae infections [140]Investigational
TopiramateEpilepsy [141]Obesity [142]Approved
Table 2. A summary of the diseases, the mechanistic rationale, and the involvement of the RAAS in their development, as well as the preclinical and clinical data collected for these diseases/indications from Section 3.
Table 2. A summary of the diseases, the mechanistic rationale, and the involvement of the RAAS in their development, as well as the preclinical and clinical data collected for these diseases/indications from Section 3.
DiseaseRAAS InvolvementPreclinical/Clinical SupportExample ARB(s)
HypertensionAntagonism with Ang II for the active site of the AT1 receptor; lower blood pressureARBs; approved drugs for hypertensionAll sartans (losartan and its active metabolite EXP3174, olmesartan, eprosartan, irbesartan, telmisartan, candesartan)
Heart FailureARBs downstream action; blockade of Ang II from AT1 receptors; Ang II binding to AT2 receptorsARBs approved for patients with HFrEF (Class I) and HFmrEF (Class IIa) who are intolerant to ACEIs and ARNICandesartan [253], valsartan [254]
Chronic Kidney DiseaseAng II through AT1R activates signaling cascades—MAPK/ERK, JNK, STAT, NF-κB, and AP-1; drives fibrosis, inflammation, cell proliferation; Ang II causes cytoskeletal disruption, ROS production, apoptosis, podocytopathy, and glomerulosclerosisARBs for patients with CKD and severely increased albuminuria (1B), moderately increased albuminuria (2C) and moderate-to-severe albuminuria and diabetes (1B)Losartan [255], irbesartan [256], and telmisartan [257]
Acute Coronary SyndromeRAS activation worsens outcomes post–MI; Ang II activates NADPH oxidase, causing oxidative injury and atherosclerosis; Ang II, AT1R, and ACE co-localize in plaques, promoting IL-6 release and instability of ARBs post-MI upregulation ARBs for patients with intolerance of ACE inhibitors, after ACS with HF symptoms, LVEF < 40%, hypertension, and/or CKDValsartan [258], losartan [259], candesartan [260]
Alzheimer’s DiseaseAng II via AT1R increases Aβ through the upregulation of APP mRNA, β-secretase activity, and presenilin expression; promotes tau phosphorylation and ROS generation, neuroinflammation, oxidative stress, neurotoxicityCandesartan: safe and reduces brain amyloid biomarkers, improves subcortical brain connectivity, and supports cognitive function in non-hypertensive individuals with prodromal Alzheimer’s diseaseTelmisartan, candesartan, losartan, and irbesartan
Parkinson’s DiseaseRegulates dopaminergic neurotransmission, blood flow, inflammatory responses; intricate interaction between Ang and DA; balance of D1, D2, AT1, AT2 receptors.Animal models of PD; neuroprotective effects of AT1R antagonists, effects driven by decrease in ROS; perindopril enhanced the effects of levodopa without causing dyskinesiasLosartan, candesartan, and telmisartan
AnxietyOveractivation of RAS through AT1R; HPA axis hyperactivity; anxiety-like behaviors; Ang II via AT1R stimulates CRH production, AVP release, adrenal catecholamine output, amplifying stress responsesClinical study: ARB-treated patients had lower anxiety STAI scores than those on ACEIs or drug-free at baseline and during the follow-upLosartan, telmisartan [261]
Cancer GliomaGlioblastoma cells express renin, angiotensinogen, renin receptor, ACE, AT1R, AT2R, renin inhibition induces apoptosis, Ang (1–7) inhibited the JNK pathway; preserved endothelial junction integrity, reduced vascular leak, and limited tumor-induced edema.Phase I clinical trial; patients with glioblastoma treated with combination of RAS modulators, treatment well tolerated; preserves quality of life/performance; may lengthen survival timeLosartan [262], telmisartan
Pathogenic InflammationCandesartan suppressed the NLRP3 inflammasome and pyroptosis in mac-rophages, reduced the expression of NLRP3 and proIL-1β by inhibiting NF-κB activation and decreasing phosphorylation of ERK1/2 and JNK1/2, lessened mitochondrial damageA meta-analysis of randomized controlled trials found that ARBs significantly reduced levels of inflammatory markers such as CRP, IL-6, and TNF-αCandesartan
CandidosisMedications targeting the RAAS inhibit secreted aspartic proteases produced by Candida albicansPreclinical studies; ARBs disrupt the metabolism and formation of Candida biofilms; decreased fungal viability at all concentrationsLosartan [223], candesartan [263]
FibrosisAng II through AT1R, TGF-β/Smad activation; ROS, inflammation; Ang (1–7) through MAS receptor inhibits fibrosis, reduces inflammation, restores tissue integrity; liver fibrosis; AT2R upregulated; antifibrotic effects by inhibition of the IRE1α-XBP1 pathwayOngoing clinical trials; ARBs in reducing fibrosis in sickle cell disease (NCT05012631), aortic stenosis (NCT04913870), AKI (NCT05272878), patients with hepatitis C and hypertension, ARB treatment, reduced fibrosis relative to untreated patients.Losartan [264], telmisartan [265], candesartan [266], valsartan [267]
Tissue Fibrosis in Systemic SclerosisAng II, fibrosis through ECM stimulationClinical study: compares the efficacy and tolerability of losartan, with nifedipine for the treatment of primary and secondary RP; tolerability of short-term treatment of RP with losartanLosartan
Diabetic Peripheral NeuropathySpinal Ang II/AT1R signaling drives neuropathic pain via p38 MAPK; losartan blockade, Ang II–driven ROS via NADPH oxidase; broader neurotoxicity of Ang II/AT1R pathwayClinical study: Bonferroni’s test indicated significantly later DPN development in the ARB and ACEI groups, beneficial to prevent DPN accompanying T2DMLosartan [268], telmisartan [269]
Inflammatory Bowel DiseasesAng II; activation of RAS; activation of JAK2/STAT1/3, elevated TH1/TH17 T-cell responses, IEC apoptosis, Ang (1–7)/MASR reduces signaling (p38/ERK/Akt)Retrospective studies of IBD patients treated with ACEIs or ARBs; encouraging results, including milder disease progression, fewer hospitalizations, reduced corticosteroid useLosartan [270], telmisartan [271], candesartan [272], valsartan [273]
Marfan SyndromeAT1R blockade in MFS mice; prevents aneurysm, reverses pathology via TGF-β/Smad suppression, AT2R; pivotal role for full therapeutic effect; required for ERK inhibitionIndividuals with Marfan syndrome who have not undergone aortic surgery; ARBs reduced the rate of aortic root Z score enlargement by roughly half, even in those also taking beta-blockers.Losartan [274], irbesartan [275], telmisartan [276]
SARS-CoV-2ARBs increase levels of ACE2 more than other hypertension medications, ACE2 entry point for SARS-CoV-2 in the nasopharynx, lungs, and heart cells; ACE2 transforms harmful Ang II into the beneficial peptides Ang (1–7) and alamandine, helps maintain balance while simultaneously preventing SARS-CoV-2 from entering through ACE2.Phase III clinical trial “CLARITY”; no evidence of benefit, based on disease severity score, for treatment with ARBs, seamless phase I and II study; intravenous infusion Angiotensin (1–7) in COVID-19 patients admitted to the ICU with severe pneumonia; in Phase II; no significant difference in OFD between groups (premature termination, further studies need to be performed)Telmisartan [277], candesartan [278]
Rheumatoid ArthritisAng II increases IL-1, IL-6, TNF-α; role in the development of RAClinical research indicates that RAS inhibitors—especially ARBs, as well as ACE inhibitors and renin inhibitors—play a role in RA by primarily targeting inflammation and oxidative stress.Losartan [279], olmesartan, candesartan, telmisartan [280]
OsteoarthritisJoint tissues; AT1R stimulation by Ang II or inflammatory cytokines (IL-1β) triggers the release of pro-inflammatory substances and MMPs, speeding up cartilage degradation and wors-ening joint injury.No clinical trials performed; one trial in patients with OA and hypertension; valsartan with strong osteoarthritis adverse reaction signals compared to irbesartan, cloxartanLosartan [281]
Opioid AddictionARBs with higher affinities for AT1R demonstrate higher affinities for µORs and ժORs than opiate ligands, such as fentanyl and naltrexoneNo ongoing clinical trialsTelmisartan [282], candesartan [283], valsartan
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Chatzipieris, F.P.; Mavromoustakou, K.; Matsoukas, J.M.; Mavromoustakos, T. Unlocking Novel Therapeutic Potential of Angiotensin II Receptor Blockers. Int. J. Mol. Sci. 2025, 26, 8819. https://doi.org/10.3390/ijms26188819

AMA Style

Chatzipieris FP, Mavromoustakou K, Matsoukas JM, Mavromoustakos T. Unlocking Novel Therapeutic Potential of Angiotensin II Receptor Blockers. International Journal of Molecular Sciences. 2025; 26(18):8819. https://doi.org/10.3390/ijms26188819

Chicago/Turabian Style

Chatzipieris, Filippos Panteleimon, Kiriaki Mavromoustakou, John M. Matsoukas, and Thomas Mavromoustakos. 2025. "Unlocking Novel Therapeutic Potential of Angiotensin II Receptor Blockers" International Journal of Molecular Sciences 26, no. 18: 8819. https://doi.org/10.3390/ijms26188819

APA Style

Chatzipieris, F. P., Mavromoustakou, K., Matsoukas, J. M., & Mavromoustakos, T. (2025). Unlocking Novel Therapeutic Potential of Angiotensin II Receptor Blockers. International Journal of Molecular Sciences, 26(18), 8819. https://doi.org/10.3390/ijms26188819

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