Pharmacologic profile of TA-606, a novel angiotensin II receptor antagonist in the rat
Pharmacologic profile of TA-606, a novel angiotensin II receptor antagonist in the rat
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DOI：
10.1097/00005344-199804000-00015
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发表时间：
1998-04-01
影响因子：
3
通讯作者：
Murata, S
中科院分区：
文献类型：
--
作者：
Hashimoto, Y;Ohashi, R;Murata, S
TA-606是一种新合成的血管紧张素II受体拮抗剂，其前药为（3-戊氧基）羰氧基甲基-5-乙酰基-2-正丙基-3-[2 '（1H-四唑-5-基）联苯-4-基]甲基-4，5，6，7-四氢咪唑并[4，5-c]吡啶-3-羧酸酯盐酸盐。在麻醉大鼠中，606 A抑制血管紧张素II诱导的加压反应，中位抑制浓度（IC 50）为6 μ g/kg，静脉注射，比氯沙坦的活性代谢物EXP 3174的效力高8倍。TA-606在Sprague-Dawley大鼠中的生物利用度比606 A高11倍，并且在自发性高血压大鼠（SHR）中具有一致的降压作用。在清醒的肾性高血压大鼠（RHR）和清醒的SHR中，TA-606降低血压，对心率无任何影响，其30 mm Hg有效剂量（ED 30）值分别为0.14和0.21 mg/kg，p.o.，分别TA-606在两种模型中的作用持续>10 h。此外，TA-606在RHR和SHR中的作用分别比氯沙坦强30倍和10倍。TA-606不影响醋酸脱氧皮质酮（DOCA）盐高血压大鼠的血压。TA-606给药12周可减轻易卒中SHR的高血压发展。这些结果表明，TA-606是一种有效的血管紧张素II受体拮抗剂，具有抗高血压疗效。因此，TA-606可能是一种有效的治疗高血压的药物。
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-3-carboxylate hydrochloride, which is a newly synthesized prodrug of 606A. In anesthetized rats, 606A inhibited angiotensin II-induced presser response with a median inhibitory concentration (IC50) of 6 mu g/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 similar to 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.