SYNTHESIS AND ANGIOTENSIN-II RECEPTOR ANTAGONIST ACTIVITY OF C-LINKED PYRIMIDINE-DERIVATIVES

The synthesis and pharmacological activity of nonpeptide angiotensin II (Ang II) receptor antagonists are presented. These 3-N-substituted pyrimidine-4(3H)-one and 4-O,N,S-substituted pyrimidine derivatives represent 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 vivo, several compounds displayed a high oral antihypertensive activity in renal hypertensive rat with decreases in systolic arterial pressure (SAP) greater than 60 mmHg 10 mg/kg. 2-[2-Methyl-4-oxo-6-n-propyl-5-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-3-yl]ethanol hydrochloride (compound 17) was compared with Losartan 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) of 60.8 mmHg, which was similar to that was observed with Losartan (maximal decrease of 60 mmHg at 3 mg/kg) with a long duration of action (greater than 16 h).