Design, Synthesis, and Biological Evaluation of Novel Imidazo[1,2-a]pyridine Derivatives as Potent c-Met Inhibitors
- ACS Med Chem Lett. 2015 Mar 2;6(5):507-12. doi: 10.1021/ml5004876.
- 1. CAS Key Laboratory of Receptor Research, and Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China.
- 2. Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 501 Haike Road, Shanghai 201203, P. R. China.
A series of imidazo[1,2-a]pyridine derivatives against c-Met was designed by means of bioisosteric replacement. In this study, a selective, potent c-Met inhibitor, 22e was identified, with IC50 values of 3.9 nM against c-Met kinase and 45.0 nM against c-Met-addicted EBC-1 cell proliferation, respectively. Compound 22e inhibited c-Met phosphorylation and downstream signaling across different oncogenic forms in c-Met overactivated Cancer cells and model cells. Compound 22e significantly inhibited tumor growth (TGI = 75%) with good oral bioavailability (F = 29%) and no significant hERG inhibition. On the basis of systematic metabolic study, the pathway of all possible metabolites of 22e in liver microsomes of different species has been proposed, and a major NADPH-dependent metabolite 33 was generated by liver microsomes. To block the metabolic site, 42 was designed and synthesized for further evaluation. Taken together, the imidazo[1,2-a]pyridine scaffold showed promising pharmacological inhibition of c-Met and warrants further investigation.