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FP-Class prostaglandin analogs have demonstrated utility for the treatment of glaucoma and ocular hypertension. A series of novel FP prostaglandin analogs was designed to optimize topical ocular activity and reduce ocular side-effects by replacing 13-carbon with oxygen. A facile synthesis was successfully developed for synthesis of the 13-oxa prostaglandins from the commercially available Corey aldehyde benzoate. Among the compounds synthesized, AL-16082 was the most potent prostaglandin FP agonist in vitro. In a prostaglandin FP receptor-linked second-messenger assay, phosphoinositide (PI) turnover, it exhibited a potency value (EC50) of 1.9 nM (78% max. response relative to fluprostenol). The isopropyl ester of AL-16082, compound AL-16049, significantly lowered intraocular pressure (IOP) in the ocular hypertensive monkey eyes by 30%. In the study of acute ocular irritation response in New Zealand albino rabbits, AL-16049 produced lower incidence of hyperemia, swelling, and discharge than PGF(2α) (1 μg), and a similar incidence of hyperemia, swelling, and discharge to latanoprost (1.8 μg). AL-16049 also produced no signs of ocular irritation or discomfort in the cat at the doses evaluated.
Dr. Z. Feng, Medicinal Chemistry, Ophthalmic Products Research, Alcon Research Ltd., 6201 South Freeway, Fort Worth, TX 76134, USA. Zixia.feng@alconlabs.com
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)