Structure-activity relationships and receptor profiles of some ocular hypotensive prostanoids.
A novel series of prostaglandin F (PGF) analogues have been prepared and evaluated in vivo and in vitro. Their intraocular pressure (IOP) lowering effects and potential side-effects, as prodrug eye drops, have been tested in cats, monkeys and rabbits. Furthermore, the PGF-analogues were tested as free acids for FP-receptor agonistic activity on cat iris sphincter. The results were compared to that of PGF2 alpha (C#1). Based on the structure-activity relationship investigations, inversion of the configuration, at carbon-9 (C#3) or carbon-11 (C#4), changes the potency and the receptor profile of PGF2 alpha. Replacement part of the omega-chain of PGF2 alpha with a benzene ring changes the potency and receptor profile of PGF2 alpha. The optimal position of the benzene ring is on carbon-17, 17-phenyl-18,19,20-trinor PGF2 alpha-isopropyl ester (C#8), and exhibited a much higher therapeutic index in the eye than PGF2 alpha or its ester. The biological activity of different substituents on the C#8 benzene ring have also been studied. Interestingly, introduction of a methyl group at positions 2 or 3 of the benzene ring (C#16 or C#17) affords compounds which are biologically more active than the methyl group at the 4-position (C#18). Furthermore, one of the analogues 13,14-dihydro-17-phenyl-18,19,20-trinor PGF2 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.
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Prostaglandin Research Laboratories, Pharmacia Upjohn, Uppsala, Sweden.
Stjernschantz
J
J
Selén
G
G
Bito
L
L
D000818:Animals; D002415:Cats; D015237:Dinoprost / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D005901:Glaucoma / Q000188:drug therapy / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects*; D011355:Prodrugs; D011817:Rabbits; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000378:metabolism*; D013329:Structure-Activity Relationship
D011355:Prodrugs; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor; D015237:Dinoprost