title: Design, Synthesis, and Biological Evaluation of Novel Imidazo[1,2-a]pyridine Derivatives as Potent c-Met Inhibitors.
abstract: 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.
authors.affiliation: 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.
authors.forename: Chunpu
authors.initials: C
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Ai
authors.affiliation: 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.
authors.forename: Dengyou
authors.initials: D
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Xia
authors.initials: X
authors.lastname: Peng
authors.affiliation: 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.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 501 Haike Road, Shanghai 201203, P. R. China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Yi
authors.initials: Y
authors.lastname: Su
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Yinchun
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 501 Haike Road, Shanghai 201203, P. R. China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
authors.affiliation: 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.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
keywords: Receptor tyrosine kinase; c-Met inhibitor; imidazo[1,2-a]pyridine; metabolic stability