Design and Optimization of a Series of 1‑Sulfonylpyrazolo[4,3‑b]pyridines as Selective c‑Met Inhibitors
journal contributionposted on 12.03.2015 by 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, Jingkang Shen
Any type of content formally published in an academic journal, usually following a peer-review process.
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 π–π 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.