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J Med Chem. 2000 Jul 13;43(14):2685-97.

Synthesis and pharmacological evaluation of new pyrazolidine-3, 5-diones as AT(1) angiotensin II receptor antagonists.

Author information

1
Institut de Chimie Pharmaceutique Albert Lespagnol and Laboratoire de Chimie Analytique, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Lille 2, rue du Professeur Laguesse, BP 83, F-59006 Lille, France. lebou001@tc.umn.edu

Abstract

On the basis of the structure of the non-peptide receptor antagonist irbesartan, a new series of AT(1) ligands was designed. In these compounds the central imidazolone nucleus of irbesartan was replaced by a pyrazolidine-3,5-dione structure. The key intermediate N-alkylpyrazolidine-3,5-diones were synthesized according to a new and general method. The most active compounds possess a spirocyclopentane ring at position 4, a linear butyl chain at position 1, and the [2'-(5-tetrazolyl)biphenyl-4-yl]methyl or [2'-(benzoylaminosulfonyl)biphenyl-4-yl]methyl group at position 2. Affinity toward the AT(1) and AT(2) receptors was assessed by the ability of the compounds to competitively displace [(3)H]AII from its specific binding sites. The most active compounds, 28 and 48, displayed high affinity for the AT(1) receptor, good selectivity AT(1) versus AT(2), and potent in vitro antagonist activity.

PMID:
10893306
DOI:
10.1021/jm9904147
[Indexed for MEDLINE]

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