SYNTHESIS AND SAR STUDIES OF NOVEL TRIAZOLOPYRIMIDINE DERIVATIVES AS POTENT, ORALLY-ACTIVE ANGIOTENSIN-II RECEPTOR ANTAGONISTS

The synthesis and pharmacological activity of new nonpeptide angiotens in II (AII) receptor antagonists are presented. These [1,2,4]-triazolo [1,5-c]pyrimidine and 1,2,4-triazolo[4,3-c]-pyrimidine derivatives rep resent a new class of bicyclic antagonists that produced a potent, ora l antihypertensive activity in the renal artery-ligated rat model. In vitro, they displayed a high affinity for rat adrenal AII receptors an d were found to be specific for the AT(1) receptor subtype. A SAR stud y has shown the importance of the 8-[2'-(1H-tetrazol-5-yl)biphenyl-4-y l]-methyl for oral activity and the critical role of alkyl substituent s at 5- and 7-positions. No significant differences were found between the [1,5-c] and [4,3-c] series. UP 269-6 ethyl]-[1,2,4]-triazolo[1,5- c]pyrimidin-2(3H)-one, derivative 29) was selected as the lead compoun d. It was shown to be a highly potent antihypertensive derivative (dec rease in mean arterial pressure of 39.6 +/- 7.2 mmHg at 1 mg/kg po in renal artery-ligated rat) with a long duration of action which display ed a high affinity for adrenal AII receptors with a marked selectivity for the AT(1) receptor subtype (K-i AT(1) = 24 nM; K-i AT(2) = 79 200 nM). This compound is currently undergoing extensive pharmacological and clinical development.