title: Pharmacological profiles of a novel non-peptide angiotensin II type I receptor antagonist HR720 in vitro and in vivo.
abstract: The 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-[Sar1,Ile8]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 AT1 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.
authors.affiliation: Department of Pharmacology, Osaka Medical College, Takatsuki, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Jin
authors.forename: K
authors.initials: K
authors.lastname: Song
authors.forename: Y
authors.initials: Y
authors.lastname: Oka
authors.forename: S
authors.initials: S
authors.lastname: Takai
authors.forename: N
authors.initials: N
authors.lastname: Shiota
authors.forename: M
authors.initials: M
authors.lastname: Miyazaki
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D000368:Aged; D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D006224:Cricetinae; D006801:Humans; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008647:Mesocricetus; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D013777:Tetrazoles / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; C094626:fonsartan; D000804:Angiotensin II; D000803:Angiotensin I; D019808:Losartan; C081643:candesartan