WP-1303 (H-1129), a novel antiglaucoma agent, lowers intraocular pressure by increasing conventional outflow in rabbits and monkeys.

Abstract

Purpose : WP-1303 (H-1129), a novel antiglaucoma agent, was reported to lower intraocular pressure (IOP) in animals by unknown mechanisms (ARVO2012 abstract, Hidaka et al.). To clarify the mechanism of the IOP lowering effects by WP-1303, we studied the effects of WP-1303 on kinase activities, the cytoskeletons of human trabecular meshwork (HTM) cells and the dynamics of aqueous humor in rabbits.

Methods : Effects of WP-1303 on kinase activities were measured by TR-FRET immunoassay. IOP was measured for up to 24 hours after a single administration of 0.03-4.0% WP-1303 in the test animals. Aqueous flow rate was determined by fluorophotometry. Total outflow facility was measured by monitoring the two-level constant pressure perfusion of the anterior chamber. Correlation of uveoscleral outflow with the IOP lowering effect of WP-1303 was estimated by indirect assessment using a topical administration of pilocarpine. The cytoskeletons of HTM cells were visualized using rhodamine-phalloidin staining.

Results : WP-1303 showed an inhibitory effect on serine/threonine kinases, including rho kinase. WP-1303 significantly lowered IOP in a dose dependent manner both in rabbits and monkeys. In rabbits, WP-1303 significantly increased total outflow facility although it did not affect aqueous flow rate and uveoscleral outflow. WP-1303 induced significant change in HTM cell shape and a decrease in actin stress fibers.

Conclusions : These results indicate that WP-1303 lowers IOP by increasing conventional outflow in association with the depolymerization of actin filaments via serine/threonine kinase inhibition.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.