Small-Molecule Drugs for Glaucoma: IOP-Lowering, Neuroprotective and Multi-Target Strategies

Abstract Glaucoma, a leading cause of irreversible blindness worldwide, is primarily driven by elevated intraocular pressure (IOP) and retinal ganglion cell (RGC) apoptosis. Small-molecule agents, owing to their high target specificity and excellent ocular tissue penetration, remain the cornerstone of clinical management. This perspective evaluates recent advances in small-molecule glaucoma therapeutics and their pharmacological targets. We first outline the medicinal chemistry, structure−activity relationships (SAR), and clinical status of agents modulating aqueous humor (AH) dynamics, detailing targeted therapies. Given that disease commonly progresses to optic nerve degeneration despite well-controlled IOP, we further summarize developmental trends in neuroprotective molecules designed to directly slow disease progression. We also discuss the rationale, design strategies, clinical translational potential and limitations of dual/multi-target drugs and combination therapies. Collectively, this perspective provides a systematic reference and future outlook for developing next-generation, mechanism-informed therapies for precision glaucoma treatment.