title: Pharmacological profile of a highly potent and long-acting angiotensin II receptor antagonist, 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4- yl]methyl]-1H-benzimidazole-7-carboxylic acid (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).
abstract: The angiotensin II (AII) antagonistic action of 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-benzi mid azole-7 - carboxylic acid (CV-11974) was examined in 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 IC50 values of 1.12 x 10(-7) and 2.86 x 10(-8) M, respectively. Similar results were obtained with EXP3174. CV-11974 interacted with AII 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]AII to subtype 2 (AT2) 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 F2 alpha 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 ID50 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.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Pharmaceutical Research Laboratories I, Takeda Chemical Industries, Ltd., Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Shibouta
authors.forename: Y
authors.initials: Y
authors.lastname: Inada
authors.forename: M
authors.initials: M
authors.lastname: Ojima
authors.forename: T
authors.initials: T
authors.lastname: Wada
authors.forename: M
authors.initials: M
authors.lastname: Noda
authors.forename: T
authors.initials: T
authors.lastname: Sanada
authors.forename: K
authors.initials: K
authors.lastname: Kubo
authors.forename: Y
authors.initials: Y
authors.lastname: Kohara
authors.forename: T
authors.initials: T
authors.lastname: Naka
authors.forename: K
authors.initials: K
authors.lastname: Nishikawa
mesh_terms: D000302:Adrenal Cortex / Q000378:metabolism; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D000805:Angiotensin III / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002417:Cattle; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D007700:Kinetics; D019808:Losartan; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D011355:Prodrugs / Q000494:pharmacology*; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D007457:Iodine Radioisotopes; D011355:Prodrugs; D013777:Tetrazoles; D000804:Angiotensin II; D000805:Angiotensin III; C066026:losartan carboxylic acid; D019808:Losartan; C077793:candesartan cilexetil; C081643:candesartan