ar-12286 and Glaucoma--Open-Angle

To evaluate the ocular hypotensive efficacy of 0.05%, 0.1% and 0.25% AR-12286 Ophthalmic Solutions in patients diagnosed with ocular hypertension or glaucoma.. Parallel comparison, vehicle-controlled, double-masked, 3-week randomized clinical trial.. Subjects (n = 89) with elevated intraocular pressure (IOP) were assigned randomly to receive either 1 of 3 concentrations of AR-12286 or its vehicle. Dosing was once-daily in the morning for 7 days, then once-daily in the evening for 7 days, then twice daily for 7 days. Primary and secondary efficacy end points were mean IOP at each diurnal time point (8 am, 10 am, 12 pm, and 4 pm) and mean change in IOP from baseline, respectively.. All 3 concentrations of AR-12286 produced statistically and clinically significant reductions in mean IOP that were dose dependent, with peak effects occurring 2 to 4 hours after dosing. Mean IOP at peak effect ranged from 17.6 to 18.7 mm Hg (-6.8 to -4.4 mm Hg) for the 3 concentrations. The largest IOP reductions were produced by 0.25% AR-12286 after twice daily dosing (up to -6.8 mm Hg; 28%). The 0.25% concentration dosed once-daily in the evening produced highly significant IOP reductions throughout the following day (-5.4 to -4.2 mm Hg). The only adverse event of note was trace (+0.5) to moderate (+2) conjunctival hyperemia that was transient, typically lasting 4 hours or less. After once-daily evening dosing, hyperemia was seen in less than 10% of patients.. AR-12286 was well tolerated and provided clinically and statistically significant ocular hypotensive efficacy in patients with ocular hypertension and glaucoma.

Topics: Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Double-Blind Method; Enzyme Inhibitors; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Isoquinolines; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; rho-Associated Kinases; Tonometry, Ocular; Treatment Outcome

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