Search Results (285)

Background/Objectives: Human carbonic anhydrase (CA) isoforms are clinically relevant zinc metalloenzymes, but their highly conserved catalytic Zn²⁺ site makes isoform-selective inhibitor design challenging. This study developed an explainable multi-isoform QSAR workflow for prioritizing selective inhibitors of human CA I, CA II, CA IX, and CA XII, integrating PubChem experimental concordance and applicability-domain (AD) analysis to distinguish model-supported candidates from exploratory extrapolative hypotheses. Methods: Curated ChEMBL K_i datasets were standardized to pK_i and modeled in KNIME using 4185 two-dimensional descriptors, Random Forest-based feature selection, and H2O.ai AutoML stacked ensembles. A matched 3200-compound four-isoform matrix supported direct selectivity profiling. Potent ChEMBL inhibitors (K_i < 10 nM) seeded 90% PubChem similarity expansion; analogues were scored across all four isoform-specific models, while PubChem records were filtered to retain only human isoform-specific K_i evidence. AD was calibrated using Morgan fingerprint similarity, descriptor-space distance, and leverage analysis. Candidates were prioritized by predicted potency, selectivity, SAR plausibility, SwissADME profile, structural alerts, and AD membership. Results: Models achieved held-out R² values of 0.727, 0.719, 0.652, and 0.607 for CA I, CA II, CA IX, and CA XII, respectively. PubChem concordance identified 1098 prioritized compounds with assay records, including 847 with direct K_i evidence and 428 with complete four-isoform coverage; same-target agreement showed Pearson r > 0.86 and linear-fit R² > 0.74. Test-set error rose from very-high-AD to low/out-of-domain classes. Conclusions: The workflow integrates QSAR prediction, PubChem concordance, explainable SAR, ADME triage, and AD-based reliability assessment. CA II and CA XII candidates showed the strongest support, CA IX showed intermediate support, and CA I candidates require cautious interpretation as low-domain exploratory hypotheses. Full article

1,2,4-Triazole derivatives are widely investigated as bioactive heterocyclic compounds with diverse biological properties; however, their potential effects on avian embryonic development remain insufficiently characterized. This study aimed to synthesize selected Mannich-type 1,2,4-triazol-5-one derivatives and evaluate their in vitro biological activities, predicted enzyme interactions, and in ovo hatchability outcomes in broiler embryos. Three derivatives (3a–3c) were synthesized and structurally characterized using Fourier-transform infrared (FT-IR), proton nuclear magnetic resonance (¹H-NMR), and carbon-13 nuclear magnetic resonance (¹³C-NMR) spectroscopy. Their reducing capacity, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity, metal-chelating capacity, and antimicrobial activity were evaluated. Molecular docking analyses were performed against carbonic anhydrase II and catalase, using acetazolamide and 3-amino-1,2,4-triazole as reference inhibitors, respectively. For the in ovo assessment, fertilized Ross 308 eggs were allocated to non-injected control, vehicle control, and compound-treated groups. Compounds 3a, 3b, and 3c were administered on incubation day 17 at 20, 10, and 5 mg/egg, respectively, as literature-supported, compound-specific exploratory exposure levels. The compounds exhibited weak reducing capacity, negligible DPPH radical-scavenging activity, pronounced metal-chelating capacity, and selective antimicrobial activity against several bacterial strains, whereas no inhibition was observed against Escherichia coli. Docking analysis predicted favorable interactions with both enzyme targets, with compound 3c showing the most favorable binding energies. Baseline egg weights were comparable among groups, indicating that initial egg weight was unlikely to influence hatchability outcomes. Complete hatch failure occurred in all compound-treated groups, whereas hatchability was observed in the control groups. These findings suggest that the tested derivatives may adversely affect embryonic development under the applied in ovo conditions. Their pronounced metal-chelating capacity, together with the predicted interactions with carbonic anhydrase II and catalase, provides a plausible mechanistic framework for interpreting the observed embryonic outcomes. The molecular docking results complement the experimental findings and provide supportive in silico evidence for these potential interactions. These findings contribute to the limited literature on the in ovo evaluation of synthetic Mannich-type 1,2,4-triazol-5-one derivatives and provide preliminary evidence regarding their embryotoxic potential. Further dose-dependent, mechanistic, histopathological, and enzyme-based studies are required to clarify the biological basis of the observed effects and to guide future evaluation of these compounds in in ovo, biomedical, and veterinary applications. Full article

Carbonic anhydrases (CAs) are zinc-containing metalloenzymes that catalyze the reversible conversion of carbon dioxide and water into bicarbonate and protons, contributing to acid–base balance, pH regulation, and ion transport. Among human cytosolic isoforms, carbonic anhydrase I (CA I) and carbonic anhydrase II (CA II) are abundant and clinically relevant, yet their distinct roles are often obscured within broader discussions of the CA family. This narrative review evaluates CA I and CA II as biomarkers and therapeutic targets in glaucoma, atherosclerosis and vascular calcification, anemia, epilepsy, Alzheimer’s disease, obstructive sleep apnea, obesity-related metabolic dysfunction, and selected cancers. CA II emerges as the more established pharmacological target, particularly in glaucoma, with acetazolamide and sultiame showing therapeutic potential in obstructive sleep apnea and possible contributions to epilepsy and neurodegeneration through pH regulation, bicarbonate-dependent signaling, and mitochondrial function. CA I instead appears more valuable as a disease-associated biomarker, especially in disorders involving erythrocyte turnover, inflammation, anemia, and malignancy, though circulating CA I may be confounded by hemolysis and altered erythrocyte dynamics. Clinical translation requires isoform-selective modulators, tissue-targeted delivery, standardized biomarker assays, and mechanistic models distinguishing primary CA involvement from secondary disease-related changes. Full article

Tumor microenvironment influences the process of tumorigenesis, with hypoxia being a characteristic of many solid tumors and an adverse prognostic factor. Carbonic anhydrases (CAs) are highly efficient zinc-containing enzymes that are overexpressed in many cancers, particularly under acidic and hypoxic conditions. CA IX expression promotes cancer cell proliferation, migration, and invasion. Vascular endothelial growth factor receptor-2 (VEGFR-2) is a tyrosine transmembrane (ΤΜ) protein regulating embryonic development, angiogenesis, tissue homeostasis and cancer. Blocking VEGFR-2 signaling is one of the most promising approaches to hindering angiogenesis and growth of cancer cells. The epidermal growth factor receptor (EGFR) is a member of the ERBB family of receptor tyrosine kinases and plays a key role in cancer progression. EGFR is uniquely found in some brain, lung and other cancers. Development of novel strategies to regulate these factors is important for the treatment of tumors. Multifunctional drugs that act on multiple pathways offer a promising approach, improving therapeutic effectiveness while reducing side effects. The present review focuses on novel compounds that inhibit CA IX and target VEGFR-2 or EGFR. Full article

Luteolin and its derivative glycosides (cynaroside, orientin and isoorientin) are compounds with a flavonoid structure of plant origin. There are different studies in the literature on the antioxidant capacities of the structures and their inhibition effects on some enzymes. In this study, the antioxidant capacities of each structure were determined comparatively, and their inhibitory effects against enzymes associated with different diseases such as acetylcholinesterase, butyrylcholinesterase, α-glycosidase and α-amylase were evaluated by comparative investigation in vitro and in silico. Antioxidant capacities were determined for each structure by iron ions (Fe³⁺), cupric ions (Cu²⁺), Fe³⁺−Triphenyltetrazolium chloride (TPTZ) reduction methods and 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), N,N-dimethyl-p-phenylenediamine (DMPD) radical scavenging methods. According to the results obtained, it was determined that the antioxidant capacities of the structures were close to or better than butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), trolox, α tocopherol and ascorbic acid, which are used as standard antioxidants. The results of the study, which was conducted to determine the inhibition effects of the structures on the determined enzymes, were found to coincide experimentally and theoretically. According to the inhibition results, the best inhibitors were found as orientin (IC₅₀: 27.729 nM) for the human carbonic anhydrase I (hCA I), cynaroside (IC₅₀: 18.24 nM) for the human carbonic anhydrase I (hCA II), isoorientin (IC₅₀: 1.93 nM) for the acetylcholinesterase (AChE), and cynaroside (IC₅₀: 6.41 and 7.15 nM) for the butyrylcholinesterase (BChE) and α-glycosidase enzymes. Additionally, absorption, distribution, metabolism, and excretion (ADME) profiles and toxicity assessments of the structures were determined in a virtual environment. Full article

A new series of isoxazole-fused thiazole–oxazole derivatives (11a–n) was rationally designed and synthesised with the aim of developing potent carbonic anhydrase (CA) I and II inhibitors. The synthesis was achieved in five steps starting from 4-bromoacetophenone, involving key intermediates such as hydroxylamine hydrochloride, hydrazine hydrate, thioisocyanate, and various phenacyl bromide derivatives, using ethanol, triethylamine, tetrahydrofuran (THF), and dimethylformamide (DMF) as solvents. The synthetic route included the formation of a β-ketoester, isoxazole ester, hydrazine adduct, thiourea derivative, and, ultimately, a thiazole ring. The structures of the final compounds were confirmed by ¹H-NMR, ¹³C-NMR, IR spectroscopy, and elemental analysis. All compounds were examined as inhibitors of human carbonic anhydrase (hCA) I and II, and all of them inhibited hCA I and hCA II. Kinetic investigation results revealed that these compounds inhibited hCA I and hCA II in a non-competitive manner. To further explore the molecular basis of their inhibitory activity, in silico studies, including molecular docking and 300 ns molecular dynamics (MD) simulations, were carried out against both CA I and CA II isoforms. These simulations provided detailed insights into the dynamic behaviour, stability, and key binding interactions of the compounds within the enzyme active sites, supporting their potential as promising carbonic anhydrase inhibitors. Full article

Background/Objectives: Carbonic anhydrase I (CAI) is a zinc-dependent metalloenzyme whose inhibitor discovery requires both effective navigation of chemical space and explicit evaluation of coordination-credible binding hypotheses. We aimed to develop an interpretable and reproducible QSAR-to-structure workflow for CAI inhibitor discovery. The workflow links potency prediction with zinc-site plausibility and early developability to support decision-oriented prioritization of new CAI inhibitor candidates. Methods: CAI inhibitors were retrieved from ChEMBL (CHEMBL261) and modeled as $p{K}_i=9-{\mathrm{l}\mathrm{o}\mathrm{g}}_{10}(K_i [\mathrm{n}\mathrm{M}\left]\right)$. AlvaDesc v3.0.8 generated 4224 2D descriptors, which were reduced using train-only preprocessing, variance filtering, correlation pruning, and bagged-tree ranking to a top-100 panel. Five regressors (elastic net, CART, bagging, GB, and XGB) were benchmarked on a held-out test set. Potent ChEMBL seeds (K_i ≤ 10 nM) were used for a 90% 2D similarity PubChem expansion. Predicted hits were then externally validated using independently available PubChem CAI $K_i$ records. Ten novel candidates lacking CAI $K_i$ data were docked to CAI (PDB: 1AZM) via SwissDock AutoDock Vina in neutral and relevant anionic states, with pose selection constrained by a Zn-donor filter (Zn-N/O $\le 2.6$ Å). SwissADME was used to profile physicochemical space, alerts, and absorption/distribution proxies. Results: The bagging model showed the best test generalization ($R^2=0.646$; RMSE = 0.61; MAE = 0.45). PFI and SHAP converged on sulfur/heteroatom connectivity and polar–lipophilic organization as dominant potency drivers. PubChem expansion yielded 25,315 analogs and 233 candidates at predicted $p{K}_i\ge 8.0$; external validation on 145 CAI-measured hits gave $R^2=0.358$ (RMSE = 0.456; MAE = 0.320). Across 20 ligand/protomer docking runs, 12 produced canonical Zn-anchored poses (10 Zn-N; 2 Zn-O). SwissADME indicated consensus logP values from −0.65 to 3.21, 0/10 PAINS alerts, and predominantly favorable drug-likeness (8/10 with zero Lipinski violations), supporting tiered advancement. Conclusions: Integrating interpretable QSAR, external PubChem validation, coordination-aware docking, and SwissADME yields a practical triage framework for CAI inhibitor discovery. The resulting tiered shortlist identifies two Zn-N-anchored N-alkyl sulfamides (CIDs 103935964 and 112684680) and one Zn-O-anchored carboxylate control (CID 122367674) as highest-priority computational hypotheses for staged biochemical evaluation. Full article

Background/Objectives: The aim of this study was to investigate the effects of intraocular pressure (IOP)-lowering drops on the sublayers of the human tear film as assessed by a novel nanometer-resolution Tear Film Imager (TFI, AdOM, Israel). Methods: In a prospective, cross-sectional study, 98 eyes from 56 adult human subjects were imaged using the TFI. The dataset included data from 18 eyes from 12 subjects treated with preserved IOP-lowering drops and 80 eyes from 44 control subjects not under ocular hypotensive therapy. Subjects in the IOP treatment group used a variety of IOP-lowering medications, including prostaglandin analogs, beta-blockers, carbonic anhydrase inhibitors, alpha agonists, and combination drops. A linear mixed effects model was used to assess the association between IOP-lowering therapy and tear film (TF) metrics, controlling for age and intra-individual correlation. The following parameters were measured: muco-aqueous layer thickness (MALT), muco-aqueous layer thinning rate (MALTR), lipid layer thickness (LLT), lipid map uniformity (LMU), inter-blink intervals (IBI), and lipid break-up time (LBUT). Results: Average ages significantly differed (p = 0.013) between the treatment group (66.5 years) and control group (average age 51.5 years), and thus results were adjusted for age accordingly. IOP was 17.1 mmHg in the treatment group and 16.1 mmHg in the control group. When analyzing the sublayers of the TF, MALTR had a significant association with IOP-lowering therapy after adjusting for age, with a difference of −52.68 nm/s; 95% confidence interval [−96.87, −8.48]; p-value = 0.020. Additionally, IBI was significantly associated with IOP-lowering therapy after log transformation (p = 0.049), with shorter IBI in the treatment group. All other metrics (MALT, LLT, LMU, and LBUT) were statistically insignificant (p > 0.05). Conclusions: These pilot results suggest that IOP-lowering drops may accelerate thinning of the TF, specifically the muco-aqueous layer. Longitudinal studies with significantly larger samples are needed to specify the differential impact of various ocular hypotensive therapies on the human TF and the clinical implications of these findings. Full article

Background: Carbonic Anhydrases (CAs) represent regulators of cell adaptation to hypoxia, pH regulation, and metabolic fitness. Among cancers, multiple myeloma (MM) is a plasma cell malignancy sustained by hypoxia-driven metabolic adaptation, extracellular acidification, and redox imbalance. Tight regulation of tumor extracellular pH, mediated by Carbonic Anhydrases IX and XII, is crucial for myeloma survival, progression, and stemness, making these isoforms attractive therapeutic targets. Methods: We designed and synthesized a library of terpenoid-based hybrids by derivatizing chlorothymol and 4-isopropyl-3-methylphenol with either the natural coumarin umbelliferon or the 2,2′-dipicolylamine (DPA) scaffold. This chemical strategy aimed to selectively inhibit tumor-associated CAs IX/XII through coumarin- or DPA-mediated recognition, while terpenoid fragments were introduced to enhance lipophilicity, membrane permeability, and potential redox-modulating properties. The compounds were tested by a Stopped-Flow assay for CA inhibition, in cell-based assays for antiproliferative properties and by means of several antioxidant assays. Results: The most active compounds, connecting the coumarin core to a terpenoid tail, inhibited the targeted CAs in the nanomolar range, showing up higher selectivity over off-target isoforms (I and II). In studies performed on MM cell lines, selected derivatives reduced viability (IC₅₀ = 15.8–85.4 µM) and displayed favorable selectivity over normal cells. In silico investigations suggested that the compounds were able to interact selectively with the target enzymes. Conclusions: Collectively, these results support a dual-targeting strategy in which selective inhibition of tumor-associated CAs, combined with redox modulation, interferes with adaptive mechanisms of MM cells, providing a rational framework for the development of multifunctional agents against metabolically resilient hematological malignancies. Full article

Selective inhibition of the tumour-associated carbonic anhydrase (CA) isoforms IX and XII, which are overexpressed in hypoxic tumours, has emerged as a promising strategy for the development of novel anticancer agents. Among the diverse CA inhibitors reported to date, coumarins have attracted particular attention. These chromenone derivatives, widely distributed in phytochemicals, display a broad range of biological activities and are known to act as suicide inhibitors of CAs. Following the tail approach, we designed a series of hybrid compounds combining a coumarin core with an N-arylthioureido scaffold located at the C-7 position and investigated how structural variations—including substituents on the coumarin and aromatic moieties, tether length, and urea/thiourea isosterism—influence their biological properties (CA inhibition and antiproliferative activity). Substituted coumarins at C-3 and C-4 were efficiently prepared via Pechmann condensation, while the thioureido motif was introduced using various aryl isothiocyanates as key synthetic intermediates. The lead compound, featuring a dimethylated coumarin, a pentyl linker, and an N-(p-tolyl)thioureido residue, inhibited the target enzymes in the low- to mid-nanomolar range (K_i = 6.0 and 49.9 nM, respectively), displaying selectivity indexes (S.I.s) surpassing those of the reference drug acetazolamide (AAZ). Moreover, it exhibited potent antiproliferative activity, with GI₅₀ values in the low micromolar range (1.9–3.5 µM) against both drug-sensitive and multidrug-resistant cancer cell lines. Label-free three-dimensional holotomographic microscopy revealed that this compound triggers slow apoptosis, leading to cell death after approximately 20 h of exposure. Full article

Coumarins represent a distinctive class of non-classical carbonic anhydrase inhibitors that interact with the entrance region of the catalytic pocket rather than directly coordinating the catalytic Zn²⁺ ion. In this study, a series of glycosylated coumarins was synthesized through a copper-catalyzed multicomponent reaction involving propargyl glycosides, salicylaldehyde, and tosyl azide, providing efficient access to iminocoumarin-based glycosides derived from natural carbohydrates. The inhibitory activity of the synthesized compounds was evaluated against human carbonic anhydrase isoforms I, II, IX, and XII using a stopped-flow CO₂ hydrase assay. The compounds showed negligible inhibition of the cytosolic isoforms hCA I and hCA II, while displaying moderate activity toward the tumor-associated isoforms hCA IX and hCA XII, with Ki values ranging from 12.9 to 41.8 μM. Among the series, 6-O-(2H-chromene-2-one-3-yl-methyl)-D-galactopyranose (10a) emerged as the most potent inhibitor of hCA IX and XII. Structure–activity relationship analysis indicated that deprotected glycosyl derivatives exhibit improved inhibitory activity compared to protected analogues. To rationalize these observations, molecular docking followed by molecular dynamics simulations and MM-GBSA binding free energy calculations were performed for both anomeric forms of compound 10a. The computational results revealed a clear preference for the β-anomer, particularly in hCA IX and XII, where favorable interactions with catalytic threonine residues and isoform-specific aromatic residues stabilize the ligand within the active-site entrance. These findings provide a molecular explanation for the experimentally observed selectivity and highlight glycosyl coumarins as potential starting points for further optimization toward selective inhibitors of tumor-associated carbonic anhydrases. Full article

The essential reaction of CO₂ hydration, fundamental to all living organisms, is facilitated by the enzyme carbonic anhydrase (CA, EC 4.2.1.1). This enzyme plays a crucial role in regulating various physiological and pathological processes. A series of heterocyclic benzenesulfonamide derivatives (19 compounds) were evaluated as possible inhibitors of human CAs. Their inhibitory properties were tested against several isoforms such as the cytosolic hCA I and hCA II, as well as the transmembrane isoforms hCA IV, hCA IX and hCA XII. The tested molecules demonstrated notable inhibitory potential, particularly toward hCA II and hCA IV, where five and four compounds, respectively, exhibited greater potency than the reference inhibitor, acetazolamide. Molecular docking simulations were further performed to elucidate the binding interactions of the most active compounds with the human CA II, IV IX and XII isoforms Full article

Multitarget-directed ligands offer a promising strategy for overcoming tumor complexity through simultaneous modulation of complementary oncogenic pathways. In this work, a novel (E)-6-(3-(4-methyl-2-thioxo-2,3-dihydrothiazol-5-yl)-3-oxoprop-1-en-1-yl)-2H-chromen-2-one (compound 6) was synthesized and evaluated as a dual inhibitor of tubulin polymerization and tumor-associated carbonic anhydrases (CAs) IX and XII. Compound 6 displayed potent antiproliferative activity, particularly against MDA-MB-231 triple-negative breast cancer cells (IC₅₀ = 0.37 µM), with excellent selectivity toward non-tumorigenic cells. Mechanistic studies demonstrated strong tubulin polymerization inhibition (IC₅₀ = 3.40 ± 0.09 µM) and submicromolar inhibition of CA IX (IC₅₀ = 0.102 ± 0.005 µM) and CA XII (IC₅₀ = 0.213 ± 0.004 µM), accompanied by downregulation of CA-IX and CA-XII protein expression. Cellular investigations revealed pronounced G₂/M phase arrest and apoptosis induction via mitochondrial signaling and caspase activation. Anti-angiogenic activity was supported by inhibition of endothelial migration and concentration-dependent suppression of VEGFR-2 (Tyr1175) phosphorylation in HUVEC cells. Human liver microsomal assays indicated measurable metabolic stability, while molecular docking and in silico ADMET predictions supported target engagement and drug-like properties. Collectively, these findings identify compound 6 as a promising multitarget anticancer lead integrating antimitotic, metabolic, and anti-angiogenic mechanisms. Full article

Background: Obstructive sleep apnea (OSA) is a highly prevalent and heterogeneous disorder associated with substantial cardiometabolic morbidity. Although continuous positive airway pressure (CPAP) remains first-line therapy, long-term effectiveness is frequently limited by suboptimal adherence. Advances in airway devices, surgical techniques, neuromodulation, and pharmacologic therapies have expanded the therapeutic landscape and created opportunities for individualized, mechanism-based treatment. Methods: We conducted a selective, narrative review with structured quantitative synthesis of randomized controlled trials, comparative cohorts, long-term follow-up studies, registries, and mechanistic investigations addressing OSA therapies beyond CPAP. Evidence spanning oral appliances, upper-airway and skeletal surgery, hypoglossal nerve stimulation, neuromuscular electrical stimulation, positional therapy, and pharmacologic interventions targeting metabolic and non-anatomical endotypes was integrated. Outcomes of interest included apnea–hypopnea index (AHI), oxygenation, blood pressure, patient-reported symptoms, durability, safety, and real-world adherence. Results: Mandibular advancement devices (MADs) consistently reduced AHI relative to placebo and produced symptom relief comparable to CPAP in mild-to-moderate OSA, largely due to superior adherence. Palatal surgery yielded meaningful short-term improvement in selected patients but demonstrated limited long-term durability. In contrast, maxillomandibular advancement (MMA) achieved the largest and most durable reductions in OSA severity, with efficacy comparable to CPAP and superior to other surgical modalities in appropriate skeletal phenotypes. Hypoglossal nerve stimulation (HNS) produced substantial, durable improvements in AHI and symptoms with high adherence, supported by randomized trials, long-term follow-up, and real-world registry data; newer bilateral and proximal stimulation systems may further broaden candidacy. Neuromuscular electrical stimulation and positional therapy provided modest, phenotype-dependent benefits, primarily as adjunctive or early-stage interventions. A major advance is the emergence of metabolic and endotype-targeted pharmacotherapy: longitudinal data demonstrate a dose-dependent relationship between weight change and OSA progression or regression, while randomized trials show that GLP-1-based therapies—particularly dual GLP-1/GIP agonism with tirzepatide—produce large, clinically meaningful reductions in AHI and cardiometabolic risk in obesity-associated OSA. Additional pharmacologic strategies targeting ventilatory loop gain and arousal threshold further support an endotype-driven treatment paradigm. Conclusions: Contemporary OSA management is shifting from a CPAP-centric model toward a precision-guided, multimodal framework that aligns therapy with dominant anatomic and physiological contributors to airway collapse. Integrating metabolic, neuromodulatory, and structural interventions—often in combination—offers the potential for durable disease control and improved patient-centered outcomes. Future priorities include head-to-head and combination trials, long-term cardiovascular outcomes, cost-effectiveness analyses, and pragmatic tools to operationalize personalized OSA therapy in routine clinical practice. Full article

Background: To evaluate the effects of preoperative topical ripasudil, a Rho-associated protein kinase (ROCK) inhibitor, on Schlemm’s canal (SC) morphology in patients with primary open-angle glaucoma (POAG). Methods: This study included 95 SC specimens obtained during trabeculectomy from 95 patients with POAG. Based on preoperative treatment, patients were divided into two groups: ripasudil (−) group (n = 68) receiving four topical medications [FP receptor agonist, β-blocker, carbonic anhydrase inhibitor (CAI), and α₂ agonist], and ripasudil (+) group (n = 27) receiving the same four medications plus ripasudil. SC morphology parameters were assessed in thrombomodulin (TBM)-stained sections, including length parameters [TBM-positive/negative and opened/closed SC lengths] and area parameters [TBM-positive/negative and opened SC areas]. Between-group comparisons were performed using unpaired t-tests, and multiple regression analysis was conducted to adjust for age, gender, preoperative intraocular pressure (IOP), and oral CAI use. Results: The ripasudil (+) group had significantly longer total SC length (TSC: 302.5 µm) than the ripasudil (−) group (273.0 µm, p = 0.023). Among area parameters, the ripasudil (+) group showed significantly larger opened SC area (OSC-A: 2689 µm² vs. 1881 µm², p = 0.008) and TBM-negative opened SC area (NOSC-A: 716 µm² vs. 305 µm², p = 0.001), whereas TBM-positive opened SC area (POSC-A) was not significantly different between groups (2001 µm² vs. 1575 µm², p = 0.096). After multivariate adjustment, ripasudil use remained significantly associated with longer TSC (p = 0.011) and larger OSC-A (p = 0.014) and NOSC-A (p = 0.001). Conclusions: Preoperative use of topical ripasudil was associated with preservation of SC lumen morphology, particularly in regions lacking SC endothelium. These findings provide a theoretical basis for therapeutic strategies employing ROCK inhibitors to maintain SC morphology and function. Full article