title: Pharmacological profile of a novel nonpeptide angiotensin II subtype 1 receptor antagonist, TCV-116.
abstract: TCV-116, an angiotensin II (AII) receptor antagonist, is a prodrug that is converted in vivo to the active form, CV-11974. CV-11974 selectively and competitively inhibited the specific binding of [125I]AII-(Sar1,lle8) to All subtype 1 (AT1) receptors in rabbit aortic membranes (Ki = 0.64 nM) and insurmountably inhibited the AII-induced maximal contractile response of rabbit aortic strips (pD'2 = 9.97). TCV-116 inhibited the AII-induced pressor response in rats (ID50 = 0.069 mg/kg. p.o.). In spontaneously hypertensive rats (SHR), TCV-116 had a sustained antihypertensive effect (ED25 = 0.68 mg/kg, p.o.). Repeated oral administration of TCV-116 (1 mg/kg) to SHR once daily for 2 weeks reduced blood pressure by 30-50 mmHg over 24 h. The antihypertensive effects of TCV-116 correlated well with the inhibition of AII-induced contractile responses of aortic strips prepared ex vivo after administration of TCV-116. TCV-116 had sustained effects in both 2 kidney, 1 clip hypertensive rats and in 1 kidney, 1 clip hypertensive rats, but had no effect in DOCA/salt hypertensive rats. Unlike enalapril, TCV-116 had no potentiating effect on the incidence of cough induced by citric acid in guinea pigs. These results suggest that TCV-116 is a promising antihypertensive agent with once daily administration.
authors.affiliation: Pharmaceutical Research Divison, Takeda Chemical Industries, Ltd., Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nishikawa
authors.forename: Y
authors.initials: Y
authors.lastname: Inada
authors.forename: Y
authors.initials: Y
authors.lastname: Shibouta
authors.forename: T
authors.initials: T
authors.lastname: Wada
authors.forename: M
authors.initials: M
authors.lastname: Ojima
authors.forename: K
authors.initials: K
authors.lastname: Kubo
authors.forename: T
authors.initials: T
authors.lastname: Naka
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D003371:Cough / Q000139:chemically induced; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006973:Hypertension / Q000188:drug therapy; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D011355:Prodrugs / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012083:Renin / Q000097:blood; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D011355:Prodrugs; D013777:Tetrazoles; D012083:Renin; C077793:candesartan cilexetil; C081643:candesartan