Discovery of potent and bioavailable GSK-3beta inhibitors

  • Bioorg Med Chem Lett. 2010 Mar 1;20(5):1693-6. doi: 10.1016/j.bmcl.2010.01.038.
Leyi Gong  1 ,  Don Hirschfeld ,  Yun-Chou Tan ,  J Heather Hogg ,  Gary Peltz ,  Zafrira Avnur ,  Pete Dunten
Affiliations
  • 1. Department of Medicinal Chemistry, Roche Palo Alto, Palo Alto, CA 94304, USA. [email protected]
PMID: 20138512 DOI: 10.1016/j.bmcl.2010.01.038
Abstract

Here we report on the discovery of a series of maleimides which have high potency and good selectivity for GSK-3beta. The incorporation of polar groups afforded compounds with good bioavailability. The most potent compound 34 has an IC(50) of 0.6nM for GSK-3beta, over 100-fold selectivity against a panel of Other Kinases, and shows efficacy in rat Osteoporosis models. The X-ray structure of GSK-3beta protein with 34 bound revealed the binding mode of the template and provided insights for future optimization opportunities.

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