SYNTHESIS AND ANGIOTENSIN-II RECEPTOR ANTAGONIST ACTIVITY OF C-LINKEDPYRAZOLE DERIVATIVES

The synthesis and pharmacological activity of new nonpeptide angiotens in II (AII) receptor antagonists are presented. These 5-O-substituted and 5-C-substituted 3-alkylpyrazole derivatives represent a new series of antagonists and have led to to the discovery of compounds with pot ent oral antihypertensive activity in a renal artery-ligated rat model . In vitro, they displayed a high affinity for rat adrenal AII recepto rs. In vivo structure-activity relationship study has shown the import ance of the 4-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl moiety for or al activity and the critical role of alkyl substituents at the 1- or 2 -position. In the case of oral administration, 5-C derivatives were fo und to be, on the whole, more potent than 5-O derivatives. UP 221-78, -(1H-tetrazol-5-yl)biphenyl-4-]methyl]-1H-pyrazole (79), displayed equ ivalent antihypertensive activity to the well known antagonist Losarta n at 3 mg/kg p.o. in renal artery-ligated rats, with maximal decreases in mean arterial pressure of 60 and 63 mmHg for Losartan and UP 221-7 8, respectively.