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A series of potent, selective, conformationally restricted angiotensin II (AII) receptor antagonists has been discovered. Two classes of conformationally restricted analogues were prepared: triazolone-based and imidazole-based biphenyl derivatives. The most active compound, an imidazole-based analogue, has an IC 50 of 11 nM and a pA 2 of 8.8.

The surmountable (competitive) N 1 -(2-methylphenyl)-2H-imidazol-2-one angiotensin II receptor antagonist SC-54628 is converted to an insurmountable (noncompetitive) antagonist SC-54629 by the addition of a methyl group at the 6-position of the phenyl ring.

We describe the pharmacologic properties of SC-52458, 5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-[2-(1H-tetrazol - 5-ylphenyl)]pyridine, a novel nonpeptide angiotensin II (AII) receptor antagonist. SC-52458 was a potent inhibitor of [125I]AII binding to AT1 receptors in rat adrenal cortex and uterine smooth muscle membranes (IC50 values of 2.8 and 6.9 nM, respectively). Contraction of rabbit aortic rings by AII was antagonized by SC-52458 in a competitive and reversible manner (pA2 of 8.18). SC-52458 had no effect on the activity of angiotensin converting enzyme (ACE) or renin in vitro. In normotensive rats, administration of SC-52458, either intravenously (i.v.) or by gavage, inhibited the pressor response to AII. Daily treatment with SC-52458 at 20, 30, and 50 mg/kg by gavage for 4 days decreased blood pressure (BP) in conscious, spontaneously hypertensive rats (SHR). Further studies in renal-artery ligated rats and sodium-deficient dogs demonstrated that oral administration of SC-52458 decreased BP and that this activity was correlated with significant plasma levels of the compound. SC-52458 is an orally active, competitive AT1-receptor antagonist with antihypertensive properties.