Ocular Hypotensive Activity and Pharmacokinetics of PF-04475270, an EP4 Prostaglandin Agonist in Preclinical Models

Abstract

Purpose: : Investigation of the ocular hypotensive activity and distribution of PF-04475270, following topical administration in preclinical models.

Methods: : The effect of PF-04475270 on IOP and ocular drug distribution was investigated in normotensive Beagle dogs following topical administration. Prodrug conversion and transcorneal permeability were assessed in rabbit corneal homogenates and human corneal epithelial cell (cHCE) model.

Results: : PF-04475270 is a prodrug of CP-734432, which stimulated cAMP formation in HEK293 cells expressing EP4 receptor and β-lactamase activity in human EP4 expressing CHO cells transfected a cAMP response element (CRE) with an EC₅₀ of 1 nM. The compound underwent rapid hydrolysis to CP-734432 in corneal homogenates, and exhibited good permeability in cHCE model The descending order of ocular exposure to CP-734432 after topical dosing of PF-04475270 in dogs was as follows: cornea > aqueous humor ≥ iris/ciliary body. The compound lowered IOP more effectively than latanoprost in the dog IOP model in single and multiple days of dosing. A maximum decrease in IOP of 20% relative to vehicle was achieved by latanoprost 12-18h post-dose, whereas that for PF-04475270 was between 30-45% at 24h post-dose.

Conclusions: : PF-04475270 is a novel ocular hypotensive compound which lowered IOP more efficaciously than latanoprost. The compound is being considered for clinical development for the treatment of glaucoma and ocular hypertension.

Keywords: intraocular pressure • receptors: pharmacology/physiology • outflow: trabecular meshwork