title: Pharmacological characterization of a novel antiglaucoma agent, Bimatoprost (AGN 192024).
abstract: Replacement of the carboxylic acid group of prostaglandin (PG) F(2alpha) with a nonacidic moiety, such as hydroxyl, methoxy, or amido, results in compounds with unique pharmacology. Bimatoprost (AGN 192024) is also a pharmacologically novel PGF(2alpha) analog, where the carboxylic acid is replaced by a neutral ethylamide substituent. Bimatoprost potently contracted the feline lung parenchymal preparation (EC(50) 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 [(3)H]17-phenyl PGF(2a) for Bimatoprost. 4) Bimatoprost pretreatment did not attenuate PGF(2alpha)-induced Ca(2+) 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 [(3)H]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.
authors.affiliation: Department of Biological Sciences, Allergan, Inc., 2525 Dupont Dr., Irvine, CA 92612, USA. woodward_david@allergan.com
authors.forename: D F
authors.initials: DF
authors.lastname: Woodward
authors.forename: A H-P
authors.initials: AH
authors.lastname: Krauss
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: Y
authors.initials: Y
authors.lastname: Liang
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.forename: C E
authors.initials: CE
authors.lastname: Protzman
authors.forename: A
authors.initials: A
authors.lastname: Bogardus
authors.forename: R
authors.initials: R
authors.lastname: Chen
authors.forename: K M
authors.initials: KM
authors.lastname: Kedzie
authors.forename: H A
authors.initials: HA
authors.lastname: Krauss
authors.forename: D W
authors.initials: DW
authors.lastname: Gil
authors.forename: A
authors.initials: A
authors.lastname: Kharlamb
authors.forename: L A
authors.initials: LA
authors.lastname: Wheeler
authors.forename: D
authors.initials: D
authors.lastname: Babusis
authors.forename: D
authors.initials: D
authors.lastname: Welty
authors.forename: D D-S
authors.initials: DD
authors.lastname: Tang-Liu
authors.forename: M
authors.initials: M
authors.lastname: Cherukury
authors.forename: S W
authors.initials: SW
authors.lastname: Andrews
authors.forename: R M
authors.initials: RM
authors.lastname: Burk
authors.forename: M E
authors.initials: ME
authors.lastname: Garst
mesh_terms: D000577:Amides; D000818:Animals; D000069580:Bimatoprost; D020013:Calcium Signaling / Q000187:drug effects; D002415:Cats; D003008:Cloprostenol / Q000031:analogs & derivatives; D003106:Colon / Q000187:drug effects; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000494:pharmacology; D005123:Eye / Q000378:metabolism; D005260:Female; D005748:Gastric Fundus / Q000187:drug effects; D017930:Genes, Reporter / Q000187:drug effects; D005849:Gerbillinae; D005901:Glaucoma / Q000188:drug therapy*; D006801:Humans; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D007429:Intraocular Pressure / Q000187:drug effects; D008055:Lipids / Q000493:pharmacokinetics / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D051381:Rats; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000096:biosynthesis
chemical_list: D000577:Amides; D007295:Inositol Phosphates; D008055:Lipids; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor; D003008:Cloprostenol; C027042:17-phenylprostaglandin F2alpha; D015237:Dinoprost; D008156:Luciferases; D000069580:Bimatoprost