Glaucoma is a leading cause of irreversible blindness worldwide, and lowering intraocular pressure (IOP) remains the only proven method to delay progression. While topical carbonic anhydrase (CA) inhibitors are established treatments, more potent and selective agents are needed. We report a series of subnanomolar and highly selective human carbonic anhydrase (hCA) II inhibitors developed through a multistage fragment growth strategy. By incrementally expanding a weakly bound sulfanilamide anchor to precisely complement the enzyme's topology, we achieved a remarkable 15,000-fold increase in potency, resulting in subnanomolar inhibition and exceptional selectivity. High-resolution X-ray crystallography revealed a distinct L-shaped configuration, effectively occupying the entire active site and establishing unique interactions with a peripheral α-helix. In rabbit glaucoma models, these inhibitors demonstrated superior IOP-lowering activity. Furthermore, the inhibitors exhibited exceptional metabolic stability, minimal ocular toxicity, and favorable safety profiles. These results demonstrate multistage fragment growth as a robust strategy for designing next-generation glaucoma therapeutics.

The purpose is to review the role of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway in glaucoma, focusing on trabecular meshwork (TM) function, aqueous humor outflow, intraocular pressure (IOP), and ocular fibrosis. A structured narrative review of PubMed/MEDLINE, Embase, and Web of Science identified peer-reviewed studies published from January 2000 to March 2026 using terms including "soluble guanylate cyclase," "sGC stimulator," "sGC activator," "cGMP," "nitric oxide," "glaucoma," "trabecular meshwork," "aqueous humor outflow," and "ocular hypertension." Experimental studies involving TM cells, Schlemm's canal endothelial cells, ocular fibroblasts, anterior segment perfusion systems, animal models, and human clinical investigations were qualitatively reviewed. Evidence supports an important role for NO-sGC-cGMP signaling in regulating conventional aqueous humor outflow. sGC activation increases intracellular cGMP and promotes protein kinase G-mediated modulation of cytoskeletal organization and RhoA/Rho kinase signaling, reducing TM contractility and increasing outflow facility. cGMP signaling may also regulate extracellular matrix remodeling and transforming growth factor-β-associated fibrotic responses in ocular tissues. Preclinical studies demonstrate enhanced outflow facility and reduced IOP after pharmacologic pathway activation. Clinical evidence is strongest for NO-donating therapies such as latanoprostene bunod, whereas direct evidence for selective sGC stimulators and activators remains limited. The NO-sGC-cGMP pathway is a promising therapeutic target in glaucoma, particularly for trabecular outflow regulation and IOP control. Despite consistent mechanistic preclinical evidence, translational challenges remain, including drug delivery, tissue-specific pharmacodynamics, and limited clinical evaluation of direct sGC modulators. Further studies are needed to define the therapeutic role of selective sGC-targeted strategies in glaucoma management.

Background/Objectives: Evaluation of real-world outcomes of standalone implantation of the third-generation trabecular micro-bypass device (iStent infinite) in eyes with mild to severe primary open-angle glaucoma (POAG). Materials: This retrospective, uncontrolled consecutive case series included eyes undergoing standalone iStent infinite implantation at a single U.S. practice. Outcomes were assessed through 12 months, including changes in intraocular pressure (IOP) and medication burden (primary), proportions achieving IOP ≤ 12/15/18 mmHg and medication categories (secondary), and safety. Subgroup analyses were completed based on preoperative IOP, glaucoma severity, and medication burden. Results: Fifty-one eyes (mean age 66.5 ± 10.8 years) were included. Mean baseline IOP was 20.1 ± 5.4 mmHg on 2.1 ± 1.2 medications. At month 12, the mean IOP decreased to 16.0 ± 3.6 mmHg (-4.1 mmHg, -20.4%; p < 0.001), and mean medications decreased to 1.5 ± 1.2 (-28.6%; p < 0.001). The proportion of eyes achieving IOP ≤ 18/15/12 mmHg increased from 41.2%/15.7%/3.9% to 79.6%/42.9%/16.3%, respectively (all p < 0.001). Medication-free eyes increased from 15.7% to 30.6%, while eyes requiring ≥ 3 medications decreased from 47.1% to 20.4%. Eyes with baseline IOP > 18 mmHg achieved greater IOP reduction (-27.8%), whereas eyes with baseline IOP ≤ 18 mmHg maintained stable IOP with reduced medications. Kaplan-Meier analysis demonstrated 12-month freedom from incisional reintervention of 92.2%. No intraoperative complications occurred. Transient self-resolving hyphema was observed in 3.9% of eyes. A secondary incisional surgery was performed in four eyes (7.8%); no vision-threatening complications were reported. Conclusions: Standalone iStent infinite implantation resulted in significant IOP and medication reductions with a favorable safety profile over 12 months, with outcomes aligned with preoperative treatment goals. These results suggest potential benefit as a less invasive real-world glaucoma intervention, warranting confirmation in larger prospective studies.