Synthesis and angiotensin II receptor antagonist activity of C-linked pyrimidine derivatives

Summary The synthesis and pharmacological activity of nonpeptide angiotensin II (Ang II) receptor antagonists are presented. These 3- N -substituted pyrimidine-4(3 H )-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 [ 125 I]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 at 10 mg/kg. 2-[2-Methyl-4-oxo-6- n -propyl-5-[[2′-(1 H -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).