Identification of 1,5-naphthyridine derivatives as a novel series of potent and selective TGF-β type I receptor inhibitors
Identification of 1,5-naphthyridine derivatives as a novel series of potent and selective TGF-β type I receptor inhibitors
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DOI：
10.1021/jm0400247
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发表时间：
2004-08-26
影响因子：
7.3
通讯作者：
Hartley, D
中科院分区：
文献类型：
--
作者：
Gellibert, FO;Woolven, J;Hartley, D
筛选命中1的优化导致新的1，5-萘啶氨基噻唑和吡唑衍生物的鉴定，其是转化生长因子-β I型受体ALK 5的有效和选择性抑制剂。化合物15和19分别以IC 50 = 6和4 nM抑制ALK 5自磷酸化，在结合和细胞测定中显示出有效的活性，并表现出对p38促分裂原活化蛋白激酶的选择性。描述了与人ALK 5复合的19的X射线晶体结构，证实了从对接研究提出的结合模式。
Optimization of the screening hit 1 led to the identification of novel 1,5-naphthyridine aminothiazole and pyrazole derivatives, which are potent and selective inhibitors of the transforming growth factor-beta type I receptor, ALK5. Compounds 15 and 19, which inhibited ALK5 autophosphorylation with IC50 = 6 and 4 nM, respectively, showed potent activities in both binding and cellular assays and exhibited selectivity over p38 mitogen-activated protein kinase. The X-ray crystal structure of 19 in complex with human ALK5 is described, confirming the binding mode proposed from docking studies.