Unknown

Dataset Information

0

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.

SUBMITTER: Li C 

PROVIDER: S-EPMC4434476 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

Design, Synthesis, and Biological Evaluation of Novel Imidazo[1,2-a]pyridine Derivatives as Potent c-Met Inhibitors.

Li Chunpu C   Ai Jing J   Zhang Dengyou D   Peng Xia X   Chen Xi X   Gao Zhiwei Z   Su Yi Y   Zhu Wei W   Ji Yinchun Y   Chen Xiaoyan X   Geng Meiyu M   Liu Hong H  

ACS medicinal chemistry letters 20150302 5

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  ...[more]

Similar Datasets

Unknown Design, Synthesis, and Biological Evaluation of 2-Substituted Aniline Pyrimidine Derivatives as Potent Dual Mer/c-Met Inhibitors.
| S-EPMC10819570 | biostudies-literature
Unknown Design of new disubstituted imidazo[1,2-<i>b</i>]pyridazine derivatives as selective Haspin inhibitors. Synthesis, binding mode and anticancer biological evaluation.
| S-EPMC7580722 | biostudies-literature
Unknown Novel Benzo[4,5]imidazo[1,2-<i>a</i>]pyrimidine derivatives as selective Cyclooxygenase-2 Inhibitors: Design, synthesis, docking studies, and biological evaluation.
| S-EPMC9870662 | biostudies-literature
Unknown Discovery of a new series of imidazo[1,2-a]pyridine compounds as selective c-Met inhibitors.
| S-EPMC4857548 | biostudies-literature
Unknown Iodine catalyzed synthesis of imidazo[1,2-<i>a</i>]pyrazine and imidazo[1,2-<i>a</i>]pyridine derivatives and their anticancer activity.
| S-EPMC10718296 | biostudies-literature
Unknown Design, Synthesis and Antimycobacterial Activity of Novel Imidazo[1,2-a]pyridine Amide-Cinnamamide Hybrids.
| S-EPMC6273240 | biostudies-literature
Unknown Design, synthesis and anti-mycobacterial evaluation of imidazo[1,2-<i>a</i>]pyridine analogues.
| S-EPMC8942254 | biostudies-literature
Unknown Multicomponent Synthesis and Binding Mode of Imidazo[1,2- a]pyridine-Capped Selective HDAC6 Inhibitors.
| S-EPMC5999327 | biostudies-literature
Unknown Design, Synthesis, and Biological Evaluation of Novel Acylhydrazone Derivatives as Potent Neuraminidase Inhibitors.
| S-EPMC7488290 | biostudies-literature
Unknown Design, Synthesis and Biological Evaluation of New Imidazo[2,1-b]Thiazole Derivatives as Selective COX-2 Inhibitors.
| S-EPMC6269562 | biostudies-literature