Design and Optimization of a Series of 1‑Sulfonylpyrazolo[4,3‑b]pyridines as Selective c‑Met Inhibitors
journal contributionposted on 12.03.2015, 00:00 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
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.