title: Nonpeptide angiotensin II antagonists derived from 1H-pyrazole-5-carboxylates and 4-aryl-1H-imidazole-5-carboxylates.
abstract: Two series of potential angiotensin II antagonists derived from carboxyl-functionalized "diazole" heterocycles have been prepared and evaluated. Initially, a limited investigation of 4-arylimidazole-5-carboxylates led to 2-n-butyl-4-(2-chlorophenyl)-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-y l] methyl]-1H-imidazole-5-carboxylic acid (12b), which was found to be a highly potent antagonist of the rabbit aorta AT1 receptor (IC50 0.55 nM). In conscious, normotensive rats, 12b at 0.1 mg/kg iv inhibited the pressor response to AII by 88%, with a duration of > 6 h. More extensively studied was an isosteric series of 3-alkyl-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazole -5- carboxylates bearing aryl, alkyl, or aralkyl substituents at N1. These compounds were available in highly regioselective fashion via condensation of a substituted hydrazine hydrochloride with a 2-(methoxyimino)-4-oxoalkanoate intermediate. In vitro, the most potent pyrazolecarboxylic acids had n-butyl at C3 and were substituted at N1 by such groups as 2,6-dichlorophenyl (19h), 2-(trifluoromethyl)phenyl (19k), benzyl (19t), and phenethyl (19u), all with IC50 values of 0.18-0.24 nM. Although less potent in the receptor assay, 3-n-propylpyrazolecarboxylic acids were at least as effective as their butyl counterparts in vivo. Several of the pyrazolecarboxylic acid derivatives demonstrated potent, long-lasting oral activity in rats. At 1 mg/kg po, the 1-benzyl-3-butyl (19t), 1-(2,6-dichlorophenyl)-3-propyl (19v), 3-propyl-1-(2,2,2-trifluoroethyl) (19y), and 1-benzyl-3-propyl (19z) analogues all gave > or = 75% inhibition of the AII pressor response in the rat model, with duration of action > 23 h.
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey 07065.
authors.forename: W T
authors.initials: WT
authors.lastname: Ashton
authors.forename: S M
authors.initials: SM
authors.lastname: Hutchins
authors.forename: W J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: G A
authors.initials: GA
authors.lastname: Doss
authors.forename: R S
authors.initials: RS
authors.lastname: Chang
authors.forename: V J
authors.initials: VJ
authors.lastname: Lotti
authors.forename: K A
authors.initials: KA
authors.lastname: Faust
authors.forename: T B
authors.initials: TB
authors.lastname: Chen
authors.forename: G J
authors.initials: GJ
authors.lastname: Zingaro
authors.forename: S D
authors.initials: SD
authors.lastname: Kivlighn
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D057911:Angiotensin Receptor Antagonists; D002264:Carboxylic Acids; D007093:Imidazoles; D011720:Pyrazoles; D000804:Angiotensin II