Synthesis and biological evaluation of 2-amino-5-aryl-3-benzylthiopyridine scaffold based potent c-Met inhibitors

A series of 2-amino-N-benzylpyridine-3-carboxnamides, 2-amino-N-benzylpyridine-3-sulfonamides and 2-amino-3-benzylthiopyridines against c-Met were designed by means of bioisosteric replacement and docking analysis. Optimization of the 2-amino-3-benzylthiopyridine scaffold identified compound (R)-10b displaying c-Met inhibition with an IC50 up to 7.7 nM. In the cytotoxic evaluation, compound (R)-10b effectively inhibited the proliferation of c-Met addictive human cancer cell lines (IC50 from 0.19 to 0.71 μM) and c-Met activation-mediated cell metastasis. Of note, (R)-10b could overcome c-Met-activation mediated gefitinib-resistance. (R)-10b could exhibit moderate inhibition of tumor growth (45%) in NIH-3T3/TPR-Met xenograft model probably due to its high clearance and low bioavailability.