Pharmacological Profiles of a Novel Non-peptide Angiotensin II Type I Receptor Antagonist HR720 In Vitro and In Vivo

Abstract

he pharmacological properties of 2-butyl-4-(methylthio)-1-[[2'' [[[(propylamino)carbonyl] amino] sulfonyl](1, 1'' biphenyl)-4-yl]methyl]-1H-imidazole-5-carboxylate (HR720), a novel non-peptide angiotensin (Ang) II type I (AT₁) receptor antagonist, were characterized in both in vitro and in vivo systems. In vitro autoradiography using ¹²⁵I-[Sar^{1, IIe8]Ang II as a ligand revealed that HR720 competitively inhibited the specific binding of the ligand to the adrenal cortex. The IC₅₀ value for the adrenal cortex was 1.5 x 10-8 M, and the IC₅₀ for medulla was 1.4 x 10-6 M. Similar results were obtained in the adrenal cortex with CV-11974, a known potent AT₁-receptor antagonist. Since AT1 receptors are known to predominate in the adrenal cortex and AT₂-receptors in the adrenal medulla, it is considered that HR720 is highly selective for AT, receptors. HR720 inhibited the Ang II-induced contraction of isolated rabbit aortic strips and human gastroepiploic arteries in a noncompetitive manner, pD''₂=9.40 and 9.62 for rabbit aorta and human artery, respectively. With CV-11974, pD''₂ values of 9.84 in isolated rabbit aorta and 10.00 in human artery were obtained. HR720 did not affect the norepinephrine-, serotonin or KCl-induced contraction even at a concentration of 1 x 10-5 M. In anesthetized hamsters, HR720 induced a dose-dependent inhibition of the pressure response to Ang II. The potency of HR720 to antagonize the Ang II-induced pressure response was similar to that of CV-11974. These results demonstrate that HR720 is a potent and selective AT₁ -receptor antagonist.}