Flesch M, Ko Y, Seul C, Düsing R, Feltkamp H, Vetter H, Sachinidis A
Medizinische Universitäts-Poliklinik, Bonn, Germany.
Eur J Pharmacol. 1995 Apr 28;289(2):399-402. doi: 10.1016/0922-4106(95)90121-3.
(+/-)-1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylate (TCV-116, Candesartan) and its active metabolite 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylic acid (CV-11974) are specific nonpeptide angiotensin AT1 receptor antagonists. In the present study, the inhibitory potency of these two antagonists on the angiotensin II-induced responses in aortic vascular smooth muscle cells from Wystar Kyoto rats was investigated. The specific binding of 125I-angiotensin II to cells was inhibited by CV-11974 and TCV-116 with a half-maximal inhibitory concentration (IC50) of 3 x 10(-11) M and 1 x 10(-9) M, respectively. CV-11974 and TCV-116 inhibited the angiotensin II-induced increase in [3H]thymidine incorporation with an IC50 of 3 x 10(-10) and 5 x 10(-9) M, respectively. Both CV-11974 and TCV-116 (10(-7) M) completely blocked the angiotensin II-induced increase in c-fos mRNA. The inhibitory potency of the metabolite CV-11974 was about 30-100-fold higher than that of the prodrug TCV-116.
（±）-1-（环己氧基羰基氧基）乙基 2-乙氧基-1-[[2'-（1H-四氮唑-5-基）联苯-4-基]甲基]-1H-苯并咪唑-7-羧酸酯（TCV-116，坎地沙坦）及其活性代谢物 2-乙氧基-1-[[2'-（1H-四氮唑-5-基）联苯-4-基]甲基]-1H-苯并咪唑-7-羧酸（CV-11974）是特异性非肽类血管紧张素 AT1 受体拮抗剂。在本研究中，研究了这两种拮抗剂对 Wystar Kyoto 大鼠主动脉血管平滑肌细胞中血管紧张素 II 诱导反应的抑制效力。CV-11974 和 TCV-116 抑制 125I-血管紧张素 II 与细胞的特异性结合，其半数最大抑制浓度（IC50）分别为 3×10^(-11) M 和 1×10^(-9) M。CV-11974 和 TCV-116 抑制血管紧张素 II 诱导的[3H]胸苷掺入，IC50 分别为 3×10^(-10) 和 5×10^(-9) M。CV-11974 和 TCV-116（10^(-7) M）均完全阻断血管紧张素 II 诱导的 c-fos mRNA 增加。代谢物 CV-11974 的抑制效力比前药 TCV-116 高约 30 - 100 倍。
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