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Abstract #3705 Published in IGR 4-2
3-Oxa-15-cyclohexyl prostaglandin DP receptor agonists as topical antiglaucoma agents
Hellberg MR; Conrow RE; Sharif NA; McLaughlin MA; Bishop JE; Crider JY; Dean WD; DeWolf KA; Pierce DR; Sallee VLBio-organic and Medicinal Chemistry 2002; 10: 2031-2049
A series of prostaglandin DP agonists containing a 3-oxa-15-cyclohexyl motif was synthesized and evaluated in several in vitro and in vivo biological assays. The reference compound ZK 118.182 (9β-chloro-15-cyclohexyl-3-oxa-Ω-pentanor PGF2α) is a potent full agonist at the prostaglandin DP receptor. Saturation of the 13,14 olefin affords AL-6556, which is less potent but is still a full agonist. Replacement of the 9-chlorine with a hydrogen atom or inversion of the carbon 15 stereochemistry also reduces affinity. In in vivo studies ZK 118.182 lowers intraocular pressure (IOP) upon topical application in the ocular hypertensive monkey. Ester, 1-alcohol, and selected amide prodrugs of the carboxylic acid enhance in vivo potency, presumably by increasing bioavailability. The clinical candidate AL-6598, the isopropyl ester prodrug of AL-6556, produces a maximum 53% drop in monkey IOP with a 1 μg dose (0.003% w/w) using a twice-daily dosing regime. Synthetically, AL-6598 was accessed from known intermediate 1 using a novel key sequence to install the cis allyl ether in the α chain, involving a selective Swern oxidative desilylation of a primary silyl ether in the presence of a secondary silyl ether. In this manner, 136 g of AL-6598 was synthesized under GMP conditions for evaluation in phase I clinical trials
Dr. P.G. Klimko, Department of Medicinal Chemistry, Alcon Research, Ltd., Pharmaceutical Products Research, 6201 South Freeway, Fort Worth, TX 76134, USA. peter.klimko@alconlabs.com
Classification:
11.4 Prostaglandins (Part of: 11 Medical treatment)
