NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS - SYNTHESIS AND BIOLOGICAL-ACTIVITY OF BENZIMIDAZOLECARBOXYLIC ACIDS
NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS - SYNTHESIS AND BIOLOGICAL-ACTIVITY OF BENZIMIDAZOLECARBOXYLIC ACIDS
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DOI：
10.1021/jm00067a016
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发表时间：
1993-07-23
影响因子：
7.3
通讯作者：
NAKA, T
中科院分区：
文献类型：
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作者：
KUBO, K;KOHARA, Y;NAKA, T
从关键中间体2-substituted-1-[(biphenyl-4-yl)methyl]-1H-benzimidazole-7-carboxylic(6a-c)制备了一系列3-amino-2-[[(biphenyl-4-yl)methyl]amino]benzoate酸，以阐明2-butyl-1-[[2‘-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic酸(CV-11194)的各种类似物的构效关系。体外实验包括AII受体结合实验和AII诱导的血管收缩实验，以及体内实验(如AII诱导的升压反应)。大多数苯并咪唑对ALL受体具有较高的亲和力(IC50值为10(-6)~10(-7)M)，并在1或3 mg/kg的剂量下抑制AII诱导的升压反应，其作用强于CV-11194和DUP753。结合亲和力和抑制AII诱导的升压反应的构效关系研究表明，一定长度的直链(如乙氧基、乙基)是最好的2位取代基，其空间因素、亲脂性和电子效应影响AII的拮抗作用。7位上的羧基和2‘位上的四唑环对于有效的口服活性的AII拮抗活性和长效降压作用都特别重要。具有代表性的化合物2-ethoxy-1-[[2‘-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-ca Rboxy acid(26b，CV-11974)可抑制[I-125]AII与牛肾上腺皮质膜的特异性结合，其IC50值为1.1×10(-7)M。CV-11974可拮抗AII引起的兔主动脉条收缩。清醒的正常血压大鼠口服CV-11974 1 mg/kg可长期抑制血管紧张素转换酶诱导的升压反应。静脉注射CV-11974 0.1~1 mg/kg可剂量依赖性降低自发性高血压大鼠的血压。
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-benzimidazole-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 All 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-ca rboxylic acid (26b, CV-11974), inhibited the specific binding of [I-125]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.