Further studies on imidazo[4,5-b] pyridine AT1 angiotensin II receptor antagonists.: Effects of the transformation of the 4-phenylquinoline backbone into 4-phenylisoquinolinone or 1-phenylindene scaffolds
Further studies on imidazo[4,5-b] pyridine AT1 angiotensin II receptor antagonists.: Effects of the transformation of the 4-phenylquinoline backbone into 4-phenylisoquinolinone or 1-phenylindene scaffolds
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DOI：
10.1021/jm0603163
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发表时间：
2006-11-02
影响因子：
7.3
通讯作者：
Vomero, Salvatore
中科院分区：
文献类型：
--
作者：
Cappelli, Andrea;Mohr, Gal. la Pericot;Vomero, Salvatore
基于Imidazo [4,5-B]吡啶部分的4-苯基喹啉片段4-用4-苯基异喹啉酮（化合物5）或1-苯基连接（化合物6）替代了吡啶基部分（化合物6），以调查结构 - 研究结构 - 活动关系。结合研究表明，大多数合成化合物表现出对AT（1）受体的高亲和力。由于羧酸5B的体外高效力，F，在渗透性（在CACO-2细胞中）和药代动力学研究中，它们与喹啉衍生物4B，I，i，j，k。研究表明，这些化合物的特征在于快速排泄，低膜渗透性和低口服生物利用度。丁烯衍生物的结构优化导致化合物6e，F具有（1）受体亲和力的有趣。优化在（1）受体配体6C处产生聚合，该聚合物形成了热可逆的聚合物（poly-6c），并通过温度依赖性动力学从后者释放。结果表明，基于新的释放机制开发新型聚合物前药的可能性。最后，将一组34个在（1）受体拮抗剂中用作评估先前发表的定性和定量药物团模型的预测能力的新测试。
The 4-phenylquinoline fragment of novel AT(1) receptor antagonists 4 based on imidazo[ 4,5-b] pyridine moiety was replaced by 4-phenylisoquinolinone (compounds 5) or 1-phenylindene (compounds 6) scaffolds to investigate the structure-activity relationships. Binding studies showed that most of the synthesized compounds display high affinity for the AT(1) receptor. Because of the in vitro high potency of carboxylic acids 5b, f, they were evaluated in permeability (in Caco-2 cells) and in pharmacokinetic studies in comparison with quinoline derivatives 4b, i, j, k. The studies showed that these compounds are characterized by rapid excretion, low membrane permeability, and low oral bioavailability. The structure optimization of the indene derivatives led to compounds 6e, f possessing interesting AT(1) receptor affinities. Optimization produced polymerizing AT(1) receptor ligand 6c, which forms a thermoreversible polymer (poly-6c) and is released from the latter by a temperature-dependent kinetics. The results suggest the possibility of developing novel polymeric prodrugs based on a new release mechanism. Finally, a set of 34 AT(1) receptor antagonists was used as a new test for the evaluation of the predictive capability of the previously published qualitative and quantitative pharmacophore models.