Kubo K, Kohara Y, Imamiya E, Sugiura Y, Inada Y, Furukawa Y, Nishikawa K, Naka T
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
J Med Chem. 1993 Jul 23;36(15):2182-95. doi: 10.1021/jm00067a016.
A series of 2-substituted-1-[(biphenyl-4-yl)methyl]-1H-benzimidazole-7- carboxylic acids was prepared from the key intermediate 3-amino-2-[[(biphenyl-4- yl)methyl]amino]benzoate (6a-c) in order to clarify the structure-activity relationships of various analogues of 2-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-ben zimidazole- 7-carboxylic acid (CV-11194), a potent and long acting angiotensin II (AII) receptor antagonist. The AII antagonistic activity of the benzimidazoles was investigated by in vitro assays, which included an AII receptor binding assay and AII-induced vasocontraction assay, as well as by in vivo assays such as an AII-induced pressor response in rats. Most of the benzimidazoles showed high affinity for the AII receptor (IC50 value, 10(-6)-10(-7) M) and inhibited the AII-induced pressor response at 1 or 3 mg/kg po, and the effects were more potent than those of CV-11194 and DuP 753. The structure-activity relationship studies on the binding affinity and the inhibition of AII-induced pressor response suggested that straight chains of a certain length (e.g., ethoxy groups, ethyl groups) were the best as substituents at the 2-position and that their steric factors, lipophilicity, and electronic effects affected the potency of the AII antagonistic action. Both a carboxyl group at the 7-position and a tetrazole ring at the 2'-position were particularly important for potent and orally active AII antagonistic activity and a long-acting hypotensive effect. The representative compound, 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylic acid (26b, CV-11974), inhibited the specific binding of [125I]AII to bovine adrenal cortical membrane with an IC50 value of 1.1 x 10(-7) M. The AII-induced contraction of rabbit aortic strips was antagonized by CV-11974 (IC50 value, 3.0 x 10(-10) M). Oral administration of CV-11974 to conscious normotensive rats at 1 mg/kg resulted in long-lasting inhibition of the AII-induced pressor response. CV-11974 at 0.1-1 mg/kg iv reduced blood pressure dose-dependently in spontaneously hypertensive rats.
为阐明2-丁基-1-[[2'-(1H-四氮唑-5-基)联苯-4-基]甲基]-1H-苯并咪唑-7-羧酸（CV-11194，一种强效长效的血管紧张素II（AII）受体拮抗剂）各种类似物的构效关系，从关键中间体3-氨基-2-[[(联苯-4-基)甲基]氨基]苯甲酸酯（6a - c）制备了一系列2-取代-1-[(联苯-4-基)甲基]-1H-苯并咪唑-7-羧酸。通过体外试验研究了苯并咪唑类的AII拮抗活性，包括AII受体结合试验和AII诱导的血管收缩试验，以及体内试验，如大鼠体内AII诱导的升压反应。大多数苯并咪唑类对AII受体表现出高亲和力（IC50值为10(-6)-10(-7) M），并在口服1或3 mg/kg时抑制AII诱导的升压反应，且效果比CV-11194和DuP 753更强。关于结合亲和力和对AII诱导的升压反应抑制作用的构效关系研究表明，一定长度的直链（如乙氧基、乙基）作为2-位取代基最佳，且其空间因素、亲脂性和电子效应影响AII拮抗作用的效力。7-位的羧基和2'-位的四氮唑环对于强效口服活性AII拮抗活性和长效降压作用尤为重要。代表性化合物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（26b，CV-11974）以1.1×10(-7) M的IC50值抑制[125I]AII与牛肾上腺皮质膜的特异性结合。CV-11974拮抗AII诱导的兔主动脉条收缩（IC50值为3.0×10(-10) M）。以1 mg/kg给清醒的正常血压大鼠口服CV-11974导致对AII诱导的升压反应的持久抑制。在自发性高血压大鼠中，静脉注射0.1 - 1 mg/kg的CV-11974可使血压剂量依赖性降低。
