A novel series of 15-fluoro prostaglandins with phenoxy termination of the omega-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 15alpha-fluoride relative stereochemistry displayed EC50 values of <or=20 nM, comparable to the value for the endogenous ligand PGF2alpha. 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-15alpha-fluoro-16-aryloxy-omega-tetranor-cis-Delta4-PGF2alpha 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 microg.