15-Fluoro prostaglandin FP agonists: a new class of topical ocular hypotensives

Graphic A novel series of 15-fluoro prostaglandins with phenoxy termination of the ω-chain was synthesized and evaluated for binding and functional activation of the prostaglandin FP receptor in vitro and for side effect potential and topical ocular hypotensive efficacy in vivo. Compounds with the 15α-fluoride relative stereochemistry displayed EC 50 values of ⩽20 nM, comparable to the value for the endogenous ligand PGF 2α. Evaluation of selected ester prodrugs of these 15-fluoro prostaglandins in vivo highlighted their generally low propensity to elicit hyperemia or ocular irritation in rabbits and efficacious intraocular pressure-lowering property in monkeys. In particular 13,14-dihydro-15-deoxy-15α-fluoro-16-aryloxy-ω-tetranor- cis-Δ 4-PGF 2α isopropyl ester ( 24) caused relatively little ocular irritation in rabbits while lowering intraocular pressure in conscious ocular hypertensive monkeys by 39% following a topical ocular dose of 3 μg.