Pharmacological profile of TH-142177, a novel orally active AT1-receptor antagonist

Summary— The pharmacological properties of TH-142177 (N-n-butyl-N-2'-(1-H-tetrazole-5-yl)biphenyl-4-yl]-methyl-(N-carboxymethyl-benzylamino)-acetamide), a novel antagonist of the angiotensin II (AII) AT₁ receptor, were studied in vitro and in vivo, and compared to those of losartan. In the rat isolated aorta, TH-142177 produced parallel shifts to the right of the concentration-response curves for AII-induced contractions without affecting the maximal response (pA₂ = 9.07). The inhibitory potency of TH-142177 in the aorta was about three times greater than that of losartan. TH-142177 completely inhibited the specific binding of ¹²⁵I]AII to AT₁ receptor in rat aortic membranes (K_i = 1.6 × 10⁻⁸ M), whereas specific ¹²⁵I]AH binding to AT₂ receptor in bovine cerebellum and human myocardium was not affected by concentrations of TH-142177 up to 10⁻⁵ M. Losartan also inhibited the ¹²⁵I] AII binding to rat aortic membranes ( K _i = 2.2 × 10⁻⁸ M). Following the intravenous administration to anesthetized normotensive rats, TH-142177 dose-dependently inhibited the increase in systolic blood pressure induced by an intravenous bolus injection of AII that was 1.5 times less potent than losartan. Furthermore, the oral administration of TH-142177 to conscious renal hypertensive rats exerted a dose-dependent reduction of systolic blood pressure without significantly effecting the heart rate. TH-142177 was at least three times more potent than losartan. These results demonstrate that TH-142177 is a potent and selective antagonist of AT₁ receptors and by oral administration has a long-lasting antihypertensive activity.