PHARMACOLOGICAL PROFILE OF A HIGHLY POTENT AND LONG-ACTING ANGIOTENSIN-II RECEPTOR ANTAGONIST, IPHENYL-4-YL]METHYL]-1H-BENZIMIDAZOLE-7-CARBOXYLIC ACID (CV-11974), AND ITS PRODRUG, (+ -)-1-(CYCLOHEXYLOXYCARBONYLOXY)-ETHYL PHENYL-4-YL]METHYL]-1H-BENZIMIDAZOLE-7-CARBOXYLATE (TCV-116)/

The angiotensin II (AII) antagonistic action of iphenyl-4-yl]methyl]-1 H-benzimidazole-7-carboxylic acid (CV-11974) was examined in in vitro assay systems, including AII receptor binding assay using membrane fra ctions of bovine adrenal cortex or rabbit aorta and AII-induced contra ction assay using rabbit aortic strips, and CV-1 1974 and its prodrug, (+/-)1-(cyclohexyloxycarbonyloxy)ethyl y-1-[[2'-(1H-tetrazol-5-yl)bip henyl-4-yl]methyl]-1 H-benzimidazole-7-carboxylate (TCV-116), were exa mined in an in vivo system of AII-induced pressor response in consciou s rats. DuP 753 or EXP3174 (the main active metabolite of DuP 753) was used as the reference compound. CV-1 1974 inhibited the binding of [I -125] All to the bovine adrenal cortical membrane and rabbit aortic me mbrane with IC50 values of 1.12 x 10(-7) and 2.86 x 10(-8) M, respecti vely. Similar results were obtained with EXP3174. CV-11974 interacted with AII in these membrane fractions with subtype 1 receptor in a comp etitive manner. CV-11974 at 10(-5) M did not affect the binding of [I- 125]AII to subtype 2 (AT2) receptor in bovine cerebellum. CV-11974 sel ectively inhibited the AII-induced contraction of rabbit aortic strips in a noncompetitive manner (pD'2, 9.97); it had no effects on the con traction induced by norepinephrine, KCl, serotonin, prostaglandin F2al pha or endothelin. EXP3174 showed a pD'2 value of 8.95 for the AII-ind uced contraction. CV-1 1974 given intravenously and TCV-116 given oral ly inhibited the AII-induced pressor response in rats with ID50 values of 0.033 mg/kg and 0.069 mg/kg, respectively. These effects of CV-119 74 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 h ighly potent and selective nonpeptide AT1 antagonist and TCV-116 has a long-acting AII antagonistic activity in vivo.