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Pharmacological profile of a highly potent and long-acting angiotensin II receptor antagonist, 2-ethoxy-1 biphenyl-4-yl-1H-benzimidazole-7-carboyxlic acid



Pharmacological profile of a highly potent and long-acting angiotensin II receptor antagonist, 2-ethoxy-1 biphenyl-4-yl-1H-benzimidazole-7-carboyxlic acid



Journal of Pharmacology & Experimental Therapeutics 266(1): 114-120



The angiotensin II (AII) antagonistic action of 2-ethoxy-1-((2'(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-benzimidazole-7-carboxylic acid (CV-11974) was examined in vitro assay systems, including AII receptor binding assay using membrane fractions of bovine adrenal cortex or rabbit aorta and AII-induced contraction assay using rabbit aortic strips, and CV-11974 and its prodrug, (+-)1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-benzimidazole-7-carboxylate (TCV-116), were examined in an in vivo system of AII-induced pressor response in conscious rats. DuP 753 or EXP3174 (the main active metabolite of DuP 753) was used as the reference compound. CV-11974 inhibited the binding of (125I) AII to the bovine adrenal cortical membrane and rabbit aortic membrane with IC-50 values of 1.1 2 times 10-7 and 2.86 times 10-8 M, respectively. Similar results were obtained with EXP3174. CV-11974 interacted with All in these membrane fractions with subtype 1 receptor in a competitive manner. CV-11974 at 10-5 M did not affect the binding of (125I)All to subtype 2 (AT-2) receptor in bovine cerebellum. CV-11974 selectively inhibited the AII induced contraction of rabbit aortic strips in a noncompetitive manner (pD'2, 9.97); it had no effects on the contraction induced by norepinephrine, KCl, serotonin, prostaglandin F-2alpha or endothelin. EXP3174 showed a pD'2 value of 8.95 for the AII-induced contraction. CV-11974 given intravenously and TCV-116 given orally inhibited the AII-induced pressor response in rats with ID-50 values of 0.033 mg/kg and 0.069 mg/kg, respectively. These effects of CV-11974 and TCV-116 were 12 and 48 times more potent than those of EXP3174 and DuP 753, respectively. These data demonstrate that CV-11974 is a highly potent and selective nonpeptide AT-1 antagonist and TCV-116 has a long-acting AII antagonistic activity in vivo.

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