Discovery of 3H-imidazo[4,5-b]pyridines as potent c-Met kinase inhibitors: design, synthesis, and biological evaluation

ChemMedChem
Danqi ChenJingkang Shen

Abstract

To identify novel c-Met inhibitors, sequences and crystal structures of the human kinome were analyzed to find interesting hinge binders that have been underexplored within the tyrosine kinase subfamily. Through this study, the imidazolopyridine ring was selected as a novel c-Met hinge-binding inhibitor scaffold. A series of derivatives was prepared, and the structure-activity relationships were studied. Among these, one compound in particular showed excellent activities in enzymatic and cellular assays, good in vitro metabolic stability, and favorable pharmacokinetic parameters. When administered orally, the compound inhibited tumor growth in an NIH-3T3/TPR-Met xenograft model and did not show adverse effects on body weight. The present work not only conceptually demonstrates a new route for designing novel kinase inhibitors by using known structural information of ligand-hinge interactions but also provides a series of imidazolopyridine derivatives as potent c-Met inhibitors.

References

Jun 20, 1986·Cell·M ParkG F Vande Woude
Mar 21, 1998·The Journal of Cell Biology·R L KlemkeD A Cheresh
Feb 21, 2002·World Journal of Gastroenterology : WJG·Q XieK Zhou
May 11, 2002·Nature Reviews. Cancer·Livio Trusolino, Paolo M Comoglio
Dec 20, 2003·Nature Reviews. Molecular Cell Biology·Carmen BirchmeierGeorge F Vande Woude
Feb 24, 2006·American Journal of Physiology. Cell Physiology·Djordje L NikolićStanislav Y Shvartsman
Oct 30, 2007·European Journal of Medicinal Chemistry·Pei-Pei KungBarbara Mroczkowski
Feb 22, 2008·Bioorganic & Medicinal Chemistry Letters·Gretchen M SchroederRobert M Borzilleri
May 16, 2008·Bioorganic & Medicinal Chemistry Letters·Zhen-Wei CaiRobert M Borzilleri
Dec 10, 2009·Science Signaling·Andrea BertottiLivio Trusolino
Dec 22, 2009·Bioorganic & Medicinal Chemistry·Stephen HiltonIan Collins
Dec 25, 2009·Trends in Molecular Medicine·Xiangdong LiuPeggy A Scherle
Nov 11, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Kenichi SudaTetsuya Mitsudomi
Feb 2, 2011·Bioorganic & Medicinal Chemistry Letters·Lalgudi S HarikrishnanAshok V Purandare
Mar 28, 2012·Bioorganic & Medicinal Chemistry Letters·Kenneth D RiceWei Xu

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Citations

Feb 23, 2013·Organic & Biomolecular Chemistry·Jonathan MacdonaldJulian Blagg
Nov 19, 2013·European Journal of Medicinal Chemistry·Ténin TraoréMichel Legraverend
Apr 26, 2016·The Journal of Organic Chemistry·Jessy AzizSandrine Piguel

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