RT Journal Article
SR Electronic
T1 Pharmacological Characterization of a Novel Antiglaucoma Agent, Bimatoprost (AGN 192024)
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 772
OP 785
DO 10.1124/jpet.102.047837
VO 305
IS 2
A1 D. F. Woodward
A1 A. H.-P. Krauss
A1 J. Chen
A1 Y. Liang
A1 C. Li
A1 C. E. Protzman
A1 A. Bogardus
A1 R. Chen
A1 K. M. Kedzie
A1 H. A. Krauss
A1 D. W. Gil
A1 A. Kharlamb
A1 L. A. Wheeler
A1 D. Babusis
A1 D. Welty
A1 D. D.-S. Tang-Liu
A1 M. Cherukury
A1 S. W. Andrews
A1 R. M. Burk
A1 M. E. Garst
YR 2003
UL http://jpet.aspetjournals.org/content/305/2/772.abstract
AB Replacement of the carboxylic acid group of prostaglandin (PG) F2α with a nonacidic moiety, such as hydroxyl, methoxy, or amido, results in compounds with unique pharmacology. Bimatoprost (AGN 192024) is also a pharmacologically novel PGF2αanalog, 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 PGF2α-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. The American Society for Pharmacology and Experimental Therapeutics