Design and Optimization of
a Series of 1‑Sulfonylpyrazolo[4,3‑<i>b</i>]pyridines as Selective c‑Met Inhibitors
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
10.1021/jm502018y.s001
https://acs.figshare.com/articles/journal_contribution/Design_and_Optimization_of_a_Series_of_1_Sulfonyl_pyrazolo_4_3_i_b_i_pyridines_as_Selective_c_Met_Inhibitors/2186710
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 <b>7</b>. By rational design, a novel sulfonylpyrazolo[4,3-<i>b</i>]pyridine <b>9</b> 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 <b>46</b> was selected as a preclinical candidate for
further anticancer drug development.
2015-03-12 00:00:00
series
DMPK properties
stability
type
sulfonyl
candidate
elaboration
moietie
Selective
cancer cells
pharmacokinetics studies
7.
activation
anticancer drug development
Optimization
potency
Series
basis
vivo
compound 46
interaction
Sulfonyl
inhibitor
cancer therapy