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2-(Alkylamino)nicotinic acid and analogs. Potent angiotensin II antagonists.

Abstract：

:A series of pyridines and other six-membered ring heterocycles connected to a biphenyltetrazole with a -CH2-NR'-link (1) were discovered to be potent angiotensin II antagonists. In the pyrimidine carboxylic acid series (W = CR, X = N, Y = CH, Z = COOH), compounds with an alkyl group (R') on the exocyclic nitrogen were much more potent than compounds with an alkyl group (R) on the heterocyclic ring. The corresponding pyridine, pyridazine, pyrazine, and 1,2,4-triazine carboxylic acids also showed potent in vitro angiotensin II antagonism. The pyridine (W, X, Y = CH, Z = COOH, R' = n-C3H7) demonstrated potent in vitro activity (pA2 = 10.10, rabbit aorta, and Ki = 0.61 nM, receptor binding in rat liver) as well as exceptional oral antihypertensive activity and bioavailability. Any nonacidic replacement for the carboxylic acid was detrimental for activity.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Winn M,De B,Zydowsky TM,Altenbach RJ,Basha FZ,Boyd SA,Brune ME,Buckner SA,Crowell D,Drizin I

doi

10.1021/jm00070a012

subject

Has Abstract,Author List Incomplete

pub_date

1993-09-03 00:00:00

pages

2676-88

issue

18

eissn

0022-2623

issn

1520-4804

journal_volume

36

pub_type

杂志文章

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