ar-12286 and Disease-Models--Animal

Inhibition of Rho kinase (ROCK) to improve fluid outflow through the trabecular meshwork and lower intraocular pressure is a strategy for the development of new anti-glaucoma agents. Alpha-aryl-beta-amino isoquinoline analogs were identified as potent ROCK inhibitors. Compounds that provided a longer duration of intraocular pressure reduction in Dutch Belted rabbits also inhibited norepinephrine transporter. Ester 60 improved bioavailability of its parent ROCK inhibitor, 29 (Ki=0.2nM) and demonstrated an effective and sustained IOP reduction for 24h after dosing. From these studies, netarsudil (a.k.a. AR-13324) was discovered and is currently in clinical trials for the treatment of glaucoma and ocular hypertension.

Topics: Animals; Benzoates; beta-Alanine; Disease Models, Animal; Drug Evaluation, Preclinical; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Molecular Structure; Norepinephrine Plasma Membrane Transport Proteins; Protein Kinase Inhibitors; Rabbits; rho-Associated Kinases; Serotonin Plasma Membrane Transport Proteins; Structure-Activity Relationship; Trabecular Meshwork