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.

Tautomer Selective Photochemistry in 1-(Tetrazol-5-yl)ethanol

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] From a fundamental point of view, tetrazoles are also particularly interesting systems, especially because of the tautomerism they may exhibit and their diversified photochemistry. 1,[21][22][23][24][25][26][27][28][29] Unsubstituted tetrazole, for example, was found to exist exclusively in the crystalline phases as the 1H-tautomer, [30][31][32] whereas in solution and gas phase 1H-and 2H-tautomers coexist, the population of the most polar 1H form increasing with the polarity of the solvent.…”

Photochemistry and Vibrational Spectra of Matrix-Isolated 5-Ethoxy-1-Phenyl-1H-Tetrazole

“…In fact, the number of patent claims and publications related to medicinal uses of tetrazoles continues to grow rapidly. [14][15][16][17][18][19] In addition, tetrazoles also show applications in agriculture, 20 in photography and photoimaging, 21 and in the automobile industry as gas-generating agents for airbags. 22 The extensive applications of tetrazole-based compounds stimulated research in areas such as the design of synthetic methodologies and the reactivity of various tetrazolyl derivatives.…”

Diverse Effects of AT1 Receptor Antagonists on Normal Blood Pressure and Regulatory System.

“…The hypotensive effects of TA-606 were 30 and 10 times more potent than those of losartan in renal hypertensive rats and spontaneously hypertensive rats, respectively (18). The antagonistic action of 606A on Ang II-induced contraction was more potent than EXP3174 in the isolated guinea pig aorta, although their binding affinities for the AT1 receptor were similar (19).…”

“…We previously demonstrated that TA-606 was a more potent antihypertensive agent than losartan in spontaneously hypertensive rats (18). Its active metabolite, 606A, also exhibited potent antihypertensive effects in spontaneously hypertensive rats (19), and induced regression of cardiac hypertrophy, augmented endothelium-dependent vascular relaxation and improved renal function in stroke-prone spontaneously hypertensive rats (20).…”