Ocular Hypotensive Activity of PF-3187207, a Nitric Oxide Donating Prostaglandin Analog, in Preclinical Models

Abstract

Purpose: : To investigate the ocular hypotensive activity and distribution of PF-3187207 following topical administration.

Methods: : The effect on IOP was investigated in cynomolgus primates with laser-induced ocular hypertension, glaucomatous Beagle dogs and rabbits using a model of transient ocular hypertension induced by intracameral administration of hypertonic saline. Nitric oxide (NO) and cGMP levels were determined in rabbit eyes following topical administration. PF-3187207 activity was compared with that of latanoprost as a reference drug.

Results: : PF-3187207 stimulated cGMP formation in PC-12 and HEK293 cells with an EC50 of 2.5 uM and 8.8 uM, respectively, thereby showing activity through the NO/cGMP pathway. NO levels in ICB and cGMP levels in ICB and aqueous humor were elevated by PF-3187207 following topical administration. These data indicate release and pharmacological activity of NO. The compound lowered IOP more effectively than latanoprost in three hypertensive animal models. In primates, a maximum decrease in IOP of 29% and 23% relative to vehicle was achieved by a single topical dose of 9 and 36 ug PF-3187207, respectively. In comparison, the peak response to latanoprost was 18% relative to vehicle obtained with a 30 ug dose. In glaucomatous Beagles, IOP decreased by 44% and 10% from baseline following a single 15 ug topical dose and vehicle, respectively. Latanoprost at the same dose lowered IOP by 27%, vehicle by 9%. Intracameral injection of hypertonic saline into rabbit eyes increased IOP transiently. Topical latanoprost did not affect this response, as expected, whereas topical PF-3187207 (30 ug) significantly blunted the hypertensive phase.

Conclusions: : In three hypertensive animal models PF-3187207 lowered IOP more efficaciously than the reference drug latanoprost presumably as a consequence of a contribution by NO in addition to its prostaglandin activity. The compound is now in clinical development for the treatment of glaucoma and ocular hypertension.

Keywords: intraocular pressure • nitric oxide • eicosanoids