Gellibert Françoise, Woolven James, Fouchet Marie-Hélène, Mathews Neil, Goodland Helen, Lovegrove Victoria, Laroze Alain, Nguyen Van-Loc, Sautet Stéphane, Wang Ruolan, Janson Cheryl, Smith Ward, Krysa Gaël, Boullay Valérie, De Gouville Anne-Charlotte, Huet Stéphane, Hartley David
Department of Medicinal Chemistry, GlaxoSmithKline, 25-27 Avenue du Québec, 91951 Les Ulis, France.
J Med Chem. 2004 Aug 26;47(18):4494-506. doi: 10.1021/jm0400247.
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.
对筛选得到的活性化合物1进行优化，得到了新型的1,5-萘啶氨基噻唑和吡唑衍生物，它们是转化生长因子-β I型受体（ALK5）的强效和选择性抑制剂。化合物15和19分别以IC50 = 6 nM和4 nM抑制ALK5自身磷酸化，在结合试验和细胞试验中均表现出强效活性，并且对p38丝裂原活化蛋白激酶具有选择性。描述了化合物19与人ALK5复合物的X射线晶体结构，证实了对接研究提出的结合模式。
