Discovery of 13-oxa prostaglandin analogs as antiglaucoma agents: synthesis and biological activity.
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 (EC(50)) 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(2alpha) (1 microg), and a similar incidence of hyperemia, swelling, and discharge to latanoprost (1.8 microg). AL-16049 also produced no signs of ocular irritation or discomfort in the cat at the doses evaluated.
Feng
Zixia
Z
Medicinal Chemistry, Ophthalmic Products Research, Alcon Research Ltd., 6201 South Freeway, Mail code: R2-39, Fort Worth, TX 76134, USA. zixia.feng@alconlabs.com
Hellberg
Mark R
MR
Sharif
Najam A
NA
McLaughlin
Marsha A
MA
Williams
Gary W
GW
Scott
Daniel
D
Wallace
Tony
T
D000287:Administration, Topical; D000818:Animals; D002415:Cats; D015237:Dinoprost / Q000494:pharmacology; D055808:Drug Discovery; D005128:Eye Diseases / Q000188:drug therapy*; D005901:Glaucoma / Q000150:complications / Q000188:drug therapy*; D000882:Haplorhini; D006973:Hypertension / Q000188:drug therapy*; D007429:Intraocular Pressure / Q000187:drug effects; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology; D011465:Prostaglandins, Synthetic / Q000009:adverse effects / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship
D011461:Prostaglandins F, Synthetic; D011465:Prostaglandins, Synthetic; C006326:fluprostenol; D015237:Dinoprost