A novel class of orally active non-peptide bradykinin B2 receptor antagonists.: 1.: Construction of the basic framework
A novel class of orally active non-peptide bradykinin B2 receptor antagonists.: 1.: Construction of the basic framework
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DOI：
10.1021/jm970591c
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发表时间：
1998-02-12
影响因子：
7.3
通讯作者：
Tanaka, H
中科院分区：
文献类型：
--
作者：
Abe, Y;Kayakiri, H;Tanaka, H
以8-苄基氧氧咪唑[1,2- α]吡啶衍生物2为起始原料，设计并合成了一类有效的、选择性的、口服活性的非肽缓激肽（BK） B-2受体拮抗剂。独特的筛选先导(2)是通过两步随机筛选过程发现的，包括识别BK和血管紧张素II （Ang II）之间的关系以及共同的结构特征。对2的系统化学修饰阐明了Bz结合亲和力所必需的结构要求，从而确定了8-[[3-（n -酰基甘酰基- n -甲氨基）-2,6-二氯苯]氧]-3-卤-2-甲基咪唑[1,2- α]吡啶骨架作为这一系列新Bz拮抗剂的基本框架。分子模拟研究表明，2,6-二氯苯环3位的n -甲基苯胺片段对这些化合物具有典型的活性构象具有关键作用。代表性先导化合物以纳米摩尔IC(50)s抑制[H-3]BK与表达Bz受体的豚鼠回肠膜制剂的特异性结合，并在口服剂量为1 mg/kg的豚鼠中显示出对BK诱导的支气管收缩的体内功能性拮抗活性。化合物47c和50b在大鼠体内的药代动力学研究突出了它们良好的口服生物利用度，表明它们是迄今为止报道的第一个口服活性纳米肽Bz拮抗剂。
A novel class of potent, selective, and orally active non-peptide bradykinin (BK) B-2 receptor antagonists were designed and synthesized starting from 8-benzyloxyimidazo[1,2-alpha]pyridine derivative 2. The unique screening lead (2) was discovered by a two-step intentional random screening process, involving recognition of the relationship between BK and angiotensin II (Ang II) and the common structural features. Systematic chemical modification of 2 elucidated the structural requirements essential for Bz binding affinity leading to the identification of 8-[[3-(N-acylglycyl-N-methylamino)-2,6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-alpha]pyridine skeleton as the basic framework of this new series of Bz antagonists. A molecular modeling study suggested the key role of the N-methylanilide moiety at the 3-position of the 2,6-dichlorobenzene ring to allow these compounds to adopt the characteristic active conformation. The representative lead compounds inhibited the specific binding of [H-3]BK to guinea pig ileum membrane preparations expressing Bz receptors, with nanomolar IC(50)s and also displayed in vivo functional antagonistic activities against BK-induced bronchoconstriction in guinea, pigs at an oral dose of 1 mg/kg. Pharmacokinetic studies of compounds 47c and 50b in rats highlighted their excellent oral bioavailabilities, indicating that they represent the first orally active nan-peptide Bz antagonists reported to date.