1. Design and Optimization of a Series of 1-Sulfonylpyrazolo[4,3-b]pyridines as Selective c-Met Inhibitors.
- Author
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Yuchi Ma, Guangqiang Sun, Danqi Chen, Xia Peng, Yue-Lei Chen, Yi Su, Yinchun Ji, Jin Liang, Xin Wang, Lin Chen, Jian Ding, Bing Xiong, Jing Ai, Meiyu Geng, and Jingkang Shen
- Subjects
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DRUG design , *PYRAZOLONES , *MET receptor , *CANCER cells , *ANTINEOPLASTIC agents , *TARGETED drug delivery , *DRUG development - Abstract
c-Met has emerged as an attractive target for targeted cancer therapy because of its abnormal activation in many cancer cells. To identify high potent and selective c-Met inhibitors, we started with profiling the potency and in vitro metabolic stability of a reported hit 7. By rational design, a novel sulfonylpyrazolo[4,3-b]pyridine 9 with improved DMPK properties was discovered. Further elaboration of p-p stacking interactions and solvent accessible polar moieties led to a series of highly potent and selective type I c-Met inhibitors. On the basis of in vitro and in vivo pharmacological and pharmacokinetics studies, compound 46 was selected as a preclinical candidate for further anticancer drug development. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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