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

The synthesis and pharmacological activity of nonpeptide angiotensin I I (Ang II) receptor antagonists are presented. These 3-N-substituted p yrimidine-4(3H)-one and 4-O,N,S-substituted pyrimidine derivatives rep resent a series of C-linked biphenyl tetrazole Ang II antagonists. In vitro, they displayed a high affinity for rat adrenal Ang II receptors , several compounds causing more than 60% displacement of [I-125]Sar(1 )-Ile(8)-Ang II from the rat adrenal Ang II receptor at 10(-7) M. In v ivo, several compounds displayed a high oral antihypertensive activity in renal hypertensive rat with decreases in systolic arterial pressur e (SAP) greater than 60 mmHg 10 mg/kg. l-5-yl)biphenyl-4-yl]methyl]pyr imidin-3-yl]ethanol hydrochloride (compound 17) was compared with Losa rtan in the renal artery-ligated rat model. It was shown that at 3 mg/ kg po, 17 induced a maximal decrease in mean arterial pressure (MAP) o f 60.8 mmHg, which was similar to that was observed with Losartan (max imal decrease of 60 mmHg at 3 mg/kg) with a long duration of action (g reater than 16 h).