title: Pharmacologic profile of TA-606, a novel angiotensin II-receptor antagonist in the rat.
abstract: This study was carried out to characterize a novel angiotensin II-receptor antagonist, TA-606, (3-pentyloxy) carbonyloxymethyl-5-acetyl-2-n-propyl-3-[2'(1H-tetrazole-5-yl) biphenyl-4-yl]methyl-4,5,6,7-tetrahydro imidazo [4,5-c] pyridine-4-carboxylate hydrochloride, which is a newly synthesized prodrug of 606A. In anesthetized rats, 606A inhibited angiotensin II-induced pressor response with a median inhibitory concentration (IC50) of 6 microg/kg, i.v., and was 8 times more potent than EXP3174, an active metabolite of losartan. Bioavailability of TA-606 was 11 times higher than that of 606A in Sprague-Dawley rats, with consistent hypotensive potencies in spontaneously hypertensive rats (SHRs). In conscious renal hypertensive rats (RHRs) and conscious SHRs, TA-606 lowered the blood pressure without any effects on the heart rate, and its effective dose for 30 mm Hg (ED30) values were 0.14 and 0.21 mg/kg, p.o., respectively. The effect of TA-606 lasted > 10 h in both models. Moreover, the effect of TA-606 was approximately 30 and 10 times more potent than those of losartan in RHRs and SHRs, respectively. TA-606 did not affect the blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. TA-606 given for 12 weeks attenuated the development of hypertension in stroke-prone SHRs. These results indicate that TA-606 is a potent angiotensin II-receptor antagonist with antihypertensive efficacy. Thus TA-606 is suggested to be a possible useful agent in the treatment of hypertension.
authors.affiliation: Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda, Saitama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: R
authors.initials: R
authors.lastname: Ohashi
authors.forename: Y
authors.initials: Y
authors.lastname: Kurosawa
authors.forename: K
authors.initials: K
authors.lastname: Minami
authors.forename: H
authors.initials: H
authors.lastname: Kaji
authors.forename: K
authors.initials: K
authors.lastname: Hayashida
authors.forename: H
authors.initials: H
authors.lastname: Narita
authors.forename: S
authors.initials: S
authors.lastname: Murata
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000097:blood / Q000494:pharmacology*; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D003900:Desoxycorticosterone; D006339:Heart Rate / Q000187:drug effects; D006977:Hypertension, Renal / Q000139:chemically induced / Q000188:drug therapy; D007093:Imidazoles / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D048289:Imidazolidines; D019808:Losartan / Q000494:pharmacology; D008297:Male; D011355:Prodrugs / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C106452:606A compound; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D007093:Imidazoles; D048289:Imidazolidines; D011355:Prodrugs; D011725:Pyridines; C112300:TA 606; D013777:Tetrazoles; D003900:Desoxycorticosterone; C065166:imidapril; D019808:Losartan