PHARMACOLOGICAL PROFILE OF TA-606, A NOVEL ANGIOTENSIN-II RECEPTOR ANTAGONIST IN THE RAT

This study was carried out to characterize a novel angiotensin II-rece ptor antagonist, TA-606, (3-pentyloxy) ethyl-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-3-carboxylate hydrochloride, which is a newly synthesiz ed prodrug of 606A. In anesthetized rats, 606A inhibited angiotensin I I-induced presser response with a median inhibitory concentration (IC5 0) of 6 mu g/kg, i.v., and was 8 times more potent than EXP3174, an ac tive metabolite of losartan. Bioavailability of TA-606 was 11 times hi gher than that of 606A in Sprague-Dawley rats, with consistent hypoten sive 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 effecti ve dose for 30 mm Hg (ED30) values were 0.14 and 0.21 mg/kg, p.o., res pectively. The effect of TA-606 lasted >10 h in both models. Moreover, the effect of TA-606 was similar to 30 and 10 times more potent than those of losartan in RHRs and SHRs, respectively. TA-606 did not affec t the blood pressure in deoxycorticosterone acetate (DOCA)-salt hypert ensive rats. TA-606 given for 12 weeks attenuated the development of h ypertension in stroke-prone SHRs. These results indicate that TA-606 i s a potent angiotensin II-receptor antagonist with antihypertensive ef ficacy. Thus TA-606 is suggested to be a possible useful agent in the treatment of hypertension.