c-Met was emerging as an attractive target for cancer-targeted therapy because deregulation of c-Met has been observed in multiple tumor types. A series of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives were designed, synthesized and evaluated for their enzymatic inhibitory activity against c-Met kinase and cellular potency against MKN45, EBC-1 and PC-3 cell lines. Nine of them showed better activity than lead compound 1 which was found via computer-aided drug design. Among them, compound 8c showed inhibitory activity of 68 nM against c-Met and low micromole cellular potency against MKN45 and EBC-1 cell lines. Moreover, 8c demonstrated more than 50-fold selectivity against other tyrosine kinases tested. The result of western blot indicated that compound 8c was capable of inhibiting the phosphorylation of c-Met kinase in MKN45 cell line in a dose-dependent manner.

由于已在多种肿瘤类型中观察到c-Met的失调，因此c-Met逐渐成为癌症靶向治疗的引人注目的靶标。设计，合成和评估了一系列4,5,6,7-四氢-1 H-吡唑并[4,3-c]吡啶衍生物对c-Met激酶的酶抑制活性和对MKN45，EBC-的细胞效力1和PC-3细胞系。它们中的九种显示出比通过计算机辅助药物设计发现的铅化合物1更好的活性。其中，化合物8c显示出对c-Met的抑制活性为68nM，并且对MKN45和EBC-1细胞系的微摩尔细胞效力低。而且8c证明对测试的其他酪氨酸激酶具有超过50倍的选择性。Western印迹的结果表明化合物8c能够以剂量依赖的方式抑制MKN45细胞系中c-Met激酶的磷酸化。