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

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Le Bourdonnec B, Meulon E, Yous S, Goossens JF, Houssin R, Henichart JP

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

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

PubMed ID

10893306 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Irbesartan	Type-1 angiotensin II receptor	Ki (nM)	2	N/A	N/A	Details