STRUCTURE-ACTIVITY-RELATIONSHIPS AND RECEPTOR PROFILES OF SOME OCULARHYPOTENSIVE PROSTANOIDS

A novel series of prostaglandin F (PGF) analogues have been prepared a nd evaluated in vivo and in vitro. Their intraocular pressure (IOP) lo wering effects and potential side-effects, as prodrug eye drops, have been tested in cats, monkeys and rabbits. Furthermore, the PGF-analogu es were tested as free acids for FP-receptor agonistic activity on cat iris sphincter. The results were compared to that of PGF(2 alpha) (C# 1). Based on the structure-activity relationship investigations, inver sion of the configuration, at carbon-9 (C#3) or carbon-ii (C#4), chang es the potency and the receptor profile of PGF(2 alpha). Replacement p art of the omega-chain of PGF(2 alpha) with a benzene ring changes the potency and receptor profile of PGF(2 alpha). The optimal position of the benzene ring is on carbon-17, 17-phenyl-18,19,20-trinor PGF(2 alp ha) isopropyl ester (C#8), and exhibited a much higher therapeutic ind ex in the eye than PGF(2 alpha) or its ester. The biological activity of different substituents on the C#8 benzene ring have also been studi ed. Interestingly, introduction of a methyl group at positions 2 or 3 of the benzene ring (C#16 or C#17) affords compounds which are biologi cally more active than the methyl group at the 4-position (C#18). Furt hermore, one of the analogues 13,14-dihydro-17-phenyl-18,19,20-trinor PGF(2 alpha)-isopropyl ester (latanoprost), has been found in clinical studies to be a highly potent and efficacious IOP-reducing agent for the treatment of glaucoma.