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

On the basis of the structure of the non-peptide receptor antagonist irbesa rtan, a new series of AT(1) ligands was designed. In these compounds the ce ntral imidazolone nucleus of irbesartan was replaced by a pyrazolidine-3,5- dione structure. The key intermediate N-alkylpyrazolidine3,5-dioneswere syn thesized according to a new and general method. The most active compounds p ossess a spirocyclopentane ring at position 4, a linear butyl chain at posi tion 1, and the [2'-(5-tetrazolyl)biphenyl-4-yl]methyl or [2'-(benzoylamino sulfonyl)biphenyl-4-yl] group at position 2. Affinity toward the AT(1) and AT(2) receptors was assessed by the ability of the compounds to competitive ly displace [H-3]AII from its specific binding sites. The most active compo unds, 28 and 48, displayed high affinity for the AT(1) receptor, good selec tivity AT(1) versus AT(2), and potent in vitro antagonist activity.