Design and Optimization of a Series of 1‑Sulfonylpyrazolo[4,3‑b]pyridines as Selective c‑Met Inhibitors
2015-03-12T00:00:00Z (GMT)
by
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.
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