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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 24, 2003; DOI: 10.1124/jpet.102.047837

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Vol. 305, Issue 2, 772-785, May 2003

Pharmacological Characterization of a Novel Antiglaucoma Agent, Bimatoprost (AGN 192024)

D. F. Woodward, A. H.-P. Krauss, J. Chen, Y. Liang, C. Li, C. E. Protzman, A. Bogardus, R. Chen, K. M. Kedzie, H. A. Krauss, D. W. Gil, A. Kharlamb, L. A. Wheeler, D. Babusis, D. Welty, D. D.-S. Tang-Liu, M. Cherukury, S. W. Andrews, R. M. Burk and M. E. Garst

Departments of Biological Sciences, Chemical Sciences, and Drug Metabolism and Pharmacokinetics, Allergan, Inc., Irvine, California

Replacement of the carboxylic acid group of prostaglandin (PG) F2alpha with a nonacidic moiety, such as hydroxyl, methoxy, or amido, results in compounds with unique pharmacology. Bimatoprost (AGN 192024) is also a pharmacologically novel PGF2alpha analog, where the carboxylic acid is replaced by a neutral ethylamide substituent. Bimatoprost potently contracted the feline lung parenchymal preparation (EC50 value of 35-55 nM) but exhibited no meaningful activity in a variety of PG-sensitive tissue and cell preparations. Its activity seemed unrelated to FP receptor stimulation according to the following evidence. 1) Bimatoprost exhibited no meaningful activity in tissues and cells containing functional FP receptors. 2) Bimatoprost activity in the cat lung parenchyma is not species-specific because its potent activity in this preparation could not be reproduced in cells stably expressing the feline FP receptor. 3) Radioligand binding studies using feline and human recombinant FP receptors exhibited minimal competition versus [3H]17-phenyl PGF2a for Bimatoprost. 4) Bimatoprost pretreatment did not attenuate PGF2alpha -induced Ca2+ signals in Swiss 3T3 cells. 5) Regional differences were apparent for Bimatoprost but not FP agonist effects in the cat lung. Bimatoprost reduced intraocular pressure in ocular normotensive and hypertensive monkeys over a 0.001 to 0.1% dose range. A single-dose and multiple-dose ocular distribution/metabolism studies using [3H]Bimatoprost (0.1%) were performed. Within the globe, bimatoprost concentrations were 10- to 100-fold higher in anterior segment tissues compared with the aqueous humor. Bimatoprost was overwhelmingly the predominant molecular species identified at all time points in ocular tissues, indicating that the intact molecule reduces intraocular pressure.

0022-3565/03/3052-0772$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


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