PHARMACOLOGY OF SC-52458, AN ORALLY-ACTIVE, NONPEPTIDE ANGIOTENSIN-AT(1) RECEPTOR ANTAGONIST

We describe the pharmacologic properties of SC-52458, yl)methyl]-2-[2- (1H-tetrazol-5-ylphenyl)]pyridine, a novel nonpeptide angiotensin II ( AII) receptor antagonist. SC-52458 was a potent inhibitor of [I-125]AI I binding to AT1 receptors in rat adrenal cortex and uterine smooth mu scle membranes (IC50 values of 2.8 and 6.9 nM, respectively). Contract ion of rabbit aortic rings by AII was antagonized by SC-52458 in a com petitive and reversible manner (pA2 of 8.18). SC-52458 had no effect o n the activity of angiotensin converting enzyme (ACE) or renin in vitr o. In normotensive rats, administration of SC-52458, either intravenou sly (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 d ecreased blood pressure (BP) in conscious, spontaneously hypertensive rats (SHR). Further studies in renal-artery ligated rats and sodium-de ficient dogs demonstrated that oral administration of SC-52458 decreas ed BP and that this activity was correlated with significant plasma le vels of the compound. SC-52458 is an orally active, competitive AT1-re ceptor antagonist with antihypertensive properties.