Characterization of angiotensin II antagonism displayed by Ib, a novel nonpeptide angiotensin AT1 receptor antagonist

The pharmacologic profile of Ib, 5-n-butyl-4-[4-[2-(1H-tetrazole-5-yl)-1H-pyrrol-1-yl]phenylmethyl)-2,4-dihydro-2-(2,6-dichloridephenyt)-3H-1,2,4-triazol-3-one, a novel nonpeptide angiotensin AT, receptor antagonist was investigated by receptor-binding studies, functional in vitro assays with rabbit and rat aorta, and in vivo experiments in rats. Ilb inhibited [I-125] angiotensin II binding to AT(1) receptors in rat liver membranes (K-i=2.5 +/- 0.5 nM) and did not interact with AT(2) receptors in bovine cerebellar membranes. In functional studies with rat and rabbit aorta, Ib inhibited the contractile response to angiotensin II (pD(2)' value: 7.43 and 7.29, respectively) with a significant reduction in the maximum. In pithed rats, Ib inhibited the angiotensin II induced pressor response in a dose-related manner. After intravenous administration, Ib produced a dose-dependent antihypertensive effects in spontaneously hypertensive rats and renal hypertensive rats. These results suggest that Ib is a potent angiotensin AT(1) selective receptor antagonist with a mode of insurmountable antagonism. (c) 2008 Elsevier B.V. All rights reserved.