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Synthesis and structure-activity relationships of nonpeptide, potent triazolone-based angiotensin II receptor antagonists.

Abstract：

:2,5-Dibutyl-2,4-dihydro-4-[[2-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4' - yl]methyl]-3H-1,2,4-triazol-3-one, SC-51316, was synthesized as a potent and orally active angiotensin II (AII) receptor antagonist with a long duration of action. To explore the lipophilic pocket in the AII receptor interacting with the substituent at the 2-position of triazolone-based antagonists, a series of compounds were prepared and evaluated for receptor binding affinity and antagonism of AII-contracted rabbit aortic rings. It has been found that the pocket is very spacious and can accommodate different sizes of lipophilic groups and various functionalities. Acidic groups generally result in a slight decrease in binding affinity. Branched chains are unfavorable. The freedom of rotation around C2-C3 in the flexible side chain is crucial for good binding. The 2-phenylethyl-substituted triazolone analogue exhibits the highest in vitro potency among all compounds that have been synthesized.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Huang HC,Reitz DB,Chamberlain TS,Olins GM,Corpus VM,McMahon EG,Palomo MA,Koepke JP,Smits GJ,McGraw DE

doi

10.1021/jm00067a015

subject

Has Abstract,Author List Incomplete

pub_date

1993-07-23 00:00:00

pages

2172-81

issue

15

eissn

0022-2623

issn

1520-4804

journal_volume

36

pub_type

杂志文章

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