Unlocking Novel Therapeutic Potential of Angiotensin II Receptor Blockers
Abstract
1. Introduction
1.1. Introducing Drug Repurposing
1.2. RAAS Physiology
1.3. Multi-Target Directed Ligand (MTDL) Approach
2. Establishing Drug Repurposing: The Example of Sildenafil
3. Repurposing Angiotensin II Receptor Blockers (ARBs)
3.1. Hypertension
3.2. Heart Failure
3.3. Chronic Kidney Disease
- 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
- 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
- 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
- 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].
3.7. Anxiety
- 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
- 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
3.10. Candidosis
3.11. Fibrosis
- 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].
3.12. Tissue Fibrosis in Systemic Sclerosis
3.13. Diabetic Peripheral Neuropathy
3.14. Inflammatory Bowel Diseases
3.15. Marfan Syndrome
- 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
3.17. Rheumatoid Arthritis
3.18. Osteoarthritis
3.19. Opioid Addiction
4. Novel Synthetic AT1 Antagonists and Dual Inhibitors
Structures of Bioactive Compounds | Biological Evaluation |
---|---|
Group A: small non-peptide molecules | |
Significant 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]. | |
Antihypertensive 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 | |
In 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]. | |
Higher 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]. | |
Compounds 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]. | |
Compound 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 | |
The 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]. | |
DHA–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 | |
Compound 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]. | |
Compound 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]. | |
Compound 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]. | |
Compound 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]. |
Structures of Bioactive Compounds | Biological Evaluation |
---|---|
Group A; Sartan Derivatives | |
In 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]. | |
In 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. | |
In 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]. | |
Oral 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]. | |
Compound 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]. | |
Compound 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]. | |
Compound 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]. | |
Compound 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]. | |
Compound 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]. |
5. Bisartans: Second-Generation Non-Peptide Mimetics of Ang II as Pan-Antiviral Drugs
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
RAAS | Renin–Angiotensin–Aldosterone system (RAAS) |
Ang I | Angiotensin I |
Ang II | Angiotensin II |
ACE | Angiotensin-converting enzyme |
AT1R | Angiotensin II Type 1 receptor |
AT2R | Angiotensin II Type 2 receptor |
MTDLs | Multi-target Directed Ligands |
HT | Hypertension |
HF | Heart Failure |
CKD | Chronic Kidney disease |
ACS | Acute Coronary Syndrome |
AD | Alzheimer’s disease |
PD | Parkinson’s disease |
RA | Rheumatoid Arthritis |
OA | Osteoarthritis |
DN | Diabetic Nephropathy |
DPN | Diabetic Peripheral Neuropathy |
SARS-CoV-2 | Severe Acute Respiratory Syndrome Coronavirus 2 |
CS | Candidosis |
FS | Fibrosis |
TFSSc | Tissue Fibrosis in Systemic Sclerosis |
RP | Raynaud’s phenomenon |
GC | Glioma Cancer |
EAE | Auto-immune encephalomyelitis |
MS | Marfan Syndrome |
MBP | Myelin Basic Protein |
IBDs | Inflammatory Bowel diseases |
TH17 | T helper 17 |
Akt | Protein kinase B |
ICU | Intensive Care Unit |
AT | Anxiety |
PI | Pathogenic Inflammation |
YU | Yet Unknown diseases |
UK | United Kingdom |
PDE5 | Phosphodiesterase-5 |
cGMP | Cyclic Guanosine Monophosphate |
NO | Nitric Oxide |
CAD | Coronary Artery disease |
CRS | Charge Relay System |
ARBs | Angiotensin II receptor blockers |
CCBs | Calcium channel blockers |
ARNIs | Angiotensin receptor neprilysin inhibitors |
ESC | European Society of Cardiology |
HFrEF | Heart Failure with Reduced Ejection Fraction |
HFmrEF | Heart Failure with Mid-Range Ejection Fraction |
KDIGO | Kidney Disease: Improving Kidney Outcomes |
APP | Amyloid precursor protein |
Aβ | Amyloid-beta |
BACE1 | Beta-site amyloid precursor protein-cleaving enzyme 1 inhibitors |
CSF | Cerebrospinal fluid |
AT4 | Angiotensin IV receptor |
ACEIs | Angiotensin-converting enzyme inhibitors |
Ang | Angiotensin |
DA | Dopamine |
ROS | Reactive Oxygen Species |
STAI | State-Trait Anxiety Inventory |
BBB | Blood–Brain Barrier |
FDA | Food and Drug Administration |
U87 | Uppsala 87 Malignant Glioma |
PCR | Polymerase Chain Reaction |
TNF-α | Tumor necrosis factor alpha |
IL-6 | Interleukin-6 |
NLRP3 | NOD-like receptor family pyrin domain containing 3 |
proIL-1β | pro-interleukin-1β |
NF-κB | Nuclear factor kappa light chain enhancer of activated B cells |
ERK1/2 | Extracellular signal-regulated kinase 1 and 2 |
JNK1/2 | c-Jun N-terminal kinase 1 and 2. to PKR, NEK7, and ASC. |
AP-1 | Activator Protein-1 |
LVEF | Left Ventricular Ejection Fraction |
PKR | Protein kinase R |
NEK7 | NIMA-related kinase 7 |
ASC | Apoptosis-associated speck-like protein containing a CARD |
T2DM | Type 2 diabetes mellitus |
FBN1 | Fibrillin-1 |
Ang (1–7) | Angiotensin (1–7) |
IL-1 | Interleukin-1 |
MMPs | Matrix metalloproteinases |
ECM | Extracellular matrix |
TGF-β | Transforming Growth Factor-β |
CVD | Cardiovascular disease |
NADPH | Nicotinamide Adenine Dinucleotide Phosphate |
MAS | MAS proto-oncogene |
IRI | Ischemia–Reperfusion Injury |
CRH | Corticotropin-releasing hormone |
AVP | Arginine Vasopressin |
STAT3 | Signal transducer and activator of transcription 3 |
MAPK | Mitogen-activated protein kinase |
CD | Crohn’s disease |
UC | Ulcerative colitis |
VEGF | Vascular endothelial growth factor |
Caspase-3 | Cysteine-aspartic acid protease 3 |
IC50 | Half-maximal inhibitory concentration |
GBM | Glioblastoma multiforme |
PBMC | Peripheral Blood Mononuclear Cells |
MHC II | Major Histocompatibility Complex Class II molecule |
Smad | Suppressor of Mothers against Decapentaplegic |
IRE1α-XBP1 | Inositol-Requiring Enzyme 1 alpha-X-Box Binding Protein 1 |
AKI | Acute Kidney Injury |
DHA | Docosahexaenoic acid |
P2Y12 | Purinergic Receptor P2Y, G-protein coupled 12 |
PAR-1 | Protease-Activated Receptor-1 |
PAF | Platelet-Activating Factor |
COX-1 | Cyclooxygenase-1 |
MD | Molecular Dynamics |
GPCRs | G protein-coupled receptors |
α1AR | α1-adrenergic receptor |
α2AR | A2-adrenergic receptor |
µ-(µOR) | μ-opioid receptor |
ժOR | δ-opioid receptor |
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Disease Area | Drug Name/Active Ingredients | Original Indication | New Indication(s) | New Indication(s) Status |
---|---|---|---|---|
Depression | Duloxetine hydrochloride | Major Depressive Disorder (MDD) [28,29] | Neuropathic pain [30], generalized anxiety disorder (GAD) [31], osteoarthritis [32], and stress incontinence [33] | Approved |
Fluoxetine hydrochloride | Major Depressive Disorder (MDD) [34] | Premenstrual dysphoric disorder (PMDD) [35] | Approved | |
Neurology | Atomoxetine hydrochloride | Parkinson’s disease (PD) [36] | Attention-deficit hyperactivity disorder (ADHD) [37] | Approved |
Bromocriptine | Parkinson’s disease [38] | Diabetes mellitus [39], prolactinomas, and other pituitary adenomas [40] | Approved | |
Chlorpromazine | Schizophrenia, bipolar disorder, and acute psychosis [41] | Breast cancer [42] | Investigational | |
Lithium | Depression, bipolar disorder [43] | Cancer [44] | Investigational | |
Penfluridol | Chronic schizophrenia, acute psychosis, and Tourette syndrome [45] | Cancer [46] | Investigational | |
Ropinirole hydrochloride | Hypertension (HTN) [47] | Parkinson’s disease (PD) [48] | Approved | |
Non-neurology | Aspirin | Analgesic, Antipyretic [49] | Antiplatelet [49], anti-thrombosis [50] | Approved |
Celecoxib | Pain, inflammation, arthritis [51] | Familial adenomatous polyposis [52] | Approved | |
Finasteride | Benign prostatic hyperplasia (BPH) [53] | Hair loss [54] | Approved | |
Losartan | Hypertension [55] | Dystrophic epidermolysis bullosa (RDEB) [56] and COVID-19 [57] | Investigational | |
Minoxidil | Hypertension (HTN) [58] | Hair loss [59] | Approved | |
Raltegravir | HIV-1 integrase Inhibitor [60] | Colorectal cancer [61] | Investigational | |
Sildenafil | Angina [26] | Erectile dysfunction (ED) and pulmonary arterial hypertension (PAH) [26] | Approved | |
Zidovudine | Failed clinical trials for cancer [62] | Human immunodeficiency virus (HIV) [62,63] | Approved | |
Cancer | Auranofin | Rheumatoid arthritis (RA) [64] | Gastrointestinal stromal tumor (GIST) [65] | Investigational |
Crizotinib | Clinical trials for anaplastic large cell lymphoma (ALCL) [66] | Non-small cell lung cancer (NSCLC) [67] | Approved | |
Imatinib | Chronic myeloid leukemia (CML) [68] | Gastrointestinal stromal tumors (GIST) [69] | Approved | |
Irinotecan hydrochloride | Colorectal cancer [70] | Pancreatic cancer [71] | Approved | |
Metformin hydrochloride | Type 2 diabetes (T2DM) [72] | Pancreatic cancer, endometrial cancer, colorectal cancer, and esophageal cancer [73,74,75,76] | Investigational | |
Nelfinavir | Human immunodeficiency virus 1 (HIV-1) [77] | Colorectal cancer, lung cancer, cervical cancer, pancreatic cancer, ovarian cancer, metastatic cancer [78] | Investigational | |
Raloxifene | Osteoporosis [79] | Breast cancer [80] | Approved | |
Rituximab | Various cancers [81] | Rheumatoid arthritis [82] | Approved | |
Sunitinib | Renal cell carcinoma (RCC) [83] and Gastrointestinal stromal tumor (GIST) [84] | Pancreatic neuroendocrine tumors (PNETs) [85] | Approved | |
Trastuzumab | Human epidermal growth factor receptor 2 (HER2)-positive breast cancer [86] | Metastatic breast cancer, gastric cancer, and early breast cancer [87,88,89] | Approved | |
Temsirolimus | Renal cell carcinoma [90] | Lung Adenocarcinoma [91] | Investigational | |
Infectious | Apmphotericin B | Antifungal [92] | Leishmaniasis [93], Mucormycosis [94] | Approved |
Dapoxetine | Premature ejaculation [95] | Zika virus infection [96] | Investigational | |
Everolimus | Immunosuppressant [97] | Pancreatic neuroendocrine tumors (PNETs) [98], renal cell carcinoma (RCC) [99], and subependymal giant cell astrocytoma (SEGA) [100] | Approved | |
Favipiravir | Influenza [101] | SARS-CoV-2 [102] | Investigational | |
Ivermectin | Antiretroviral [103] | SARS-CoV-2 [104] | Investigational | |
Ketoconazole | Fungal infections [105] | Cushing’s syndrome [106] | Approved | |
Remdesivir | Antiviral [107] | SARS-CoV-2 [107] | Approved | |
Sirolimus | Organ rejection in patients receiving renal transplants [108] | Malaria [109] | Investigational | |
Thalidomide | Morning sickness (withdrawn) [67] | Erythema nodosum leprosum (Leprosy) [110] and Multiple Myeloma [111] | Approved | |
Rare and orphan | Alefacept | Chronic plaque psoriasis [112] | Memory T cell-mediated autoimmune diseases, organ transplantation and type I diabetes (T1D) [113] | Investigational |
Baclofen | Muscle relaxant [114] | Alcohol use disorder [115] | Approved | |
Clobetasol | Psoriasis [116] | post-cataract surgery pain and inflammation [117] | Approved | |
Dimethyl fumarate | Multiple sclerosis [118] | Psoriasis [119], anti-inflammatory [120] | Approved | |
Erythropoietin | Anemia [121] | Traumatic brain injury [122] | Investigational | |
Ethinyl estradiol | Turner syndrome [123] | Contraceptive applications [124], acne, hirsutism [125] | Approved | |
Fingolimod | Multiple sclerosis (MS) [126] | Alzheimer’s disease [127], cancer [128], diabetic retinopathy [129] | Investigational | |
Liraglutide | Diabetes [130] | Alzheimer’s disease (AD) [131] | Investigational | |
N-acetyl cysteine | Mucolytic agent [132] | Obsessive–compulsive disorder [133] | Investigational | |
Pregabalin | Neuropathic pain [134] | Generalized anxiety disorder [135] | Approved | |
Simvastatin | Cardiovascular diseases [136] | Anti-tumor agents [137], neurodegenerative disorders [138], preterm labor [139] and Klebsiella pneumoniae infections [140] | Investigational | |
Topiramate | Epilepsy [141] | Obesity [142] | Approved |
Disease | RAAS Involvement | Preclinical/Clinical Support | Example ARB(s) |
---|---|---|---|
Hypertension | Antagonism with Ang II for the active site of the AT1 receptor; lower blood pressure | ARBs; approved drugs for hypertension | All sartans (losartan and its active metabolite EXP3174, olmesartan, eprosartan, irbesartan, telmisartan, candesartan) |
Heart Failure | ARBs downstream action; blockade of Ang II from AT1 receptors; Ang II binding to AT2 receptors | ARBs approved for patients with HFrEF (Class I) and HFmrEF (Class IIa) who are intolerant to ACEIs and ARNI | Candesartan [253], valsartan [254] |
Chronic Kidney Disease | Ang 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 glomerulosclerosis | ARBs 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 Syndrome | RAS 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 CKD | Valsartan [258], losartan [259], candesartan [260] |
Alzheimer’s Disease | Ang 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, neurotoxicity | Candesartan: safe and reduces brain amyloid biomarkers, improves subcortical brain connectivity, and supports cognitive function in non-hypertensive individuals with prodromal Alzheimer’s disease | Telmisartan, candesartan, losartan, and irbesartan |
Parkinson’s Disease | Regulates 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 dyskinesias | Losartan, candesartan, and telmisartan |
Anxiety | Overactivation of RAS through AT1R; HPA axis hyperactivity; anxiety-like behaviors; Ang II via AT1R stimulates CRH production, AVP release, adrenal catecholamine output, amplifying stress responses | Clinical study: ARB-treated patients had lower anxiety STAI scores than those on ACEIs or drug-free at baseline and during the follow-up | Losartan, telmisartan [261] |
Cancer Glioma | Glioblastoma 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 time | Losartan [262], telmisartan |
Pathogenic Inflammation | Candesartan 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 damage | A meta-analysis of randomized controlled trials found that ARBs significantly reduced levels of inflammatory markers such as CRP, IL-6, and TNF-α | Candesartan |
Candidosis | Medications targeting the RAAS inhibit secreted aspartic proteases produced by Candida albicans | Preclinical studies; ARBs disrupt the metabolism and formation of Candida biofilms; decreased fungal viability at all concentrations | Losartan [223], candesartan [263] |
Fibrosis | Ang 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 pathway | Ongoing 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 Sclerosis | Ang II, fibrosis through ECM stimulation | Clinical 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 losartan | Losartan |
Diabetic Peripheral Neuropathy | Spinal 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 pathway | Clinical study: Bonferroni’s test indicated significantly later DPN development in the ARB and ACEI groups, beneficial to prevent DPN accompanying T2DM | Losartan [268], telmisartan [269] |
Inflammatory Bowel Diseases | Ang 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 use | Losartan [270], telmisartan [271], candesartan [272], valsartan [273] |
Marfan Syndrome | AT1R blockade in MFS mice; prevents aneurysm, reverses pathology via TGF-β/Smad suppression, AT2R; pivotal role for full therapeutic effect; required for ERK inhibition | Individuals 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-2 | ARBs 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 Arthritis | Ang II increases IL-1, IL-6, TNF-α; role in the development of RA | Clinical 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] |
Osteoarthritis | Joint 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, cloxartan | Losartan [281] |
Opioid Addiction | ARBs with higher affinities for AT1R demonstrate higher affinities for µORs and ժORs than opiate ligands, such as fentanyl and naltrexone | No ongoing clinical trials | Telmisartan [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
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 StyleChatzipieris, 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 StyleChatzipieris, 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