Discovery of potent and bioavailable GSK-3beta inhibitors

Leyi Gong; Don Hirschfeld; Yun-Chou Tan; J Heather Hogg; Gary Peltz; Zafrira Avnur; Pete Dunten

doi:10.1016/j.bmcl.2010.01.038

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. Epub 2010 Jan 25.

Authors

Leyi Gong¹, Don Hirschfeld, Yun-Chou Tan, J Heather Hogg, Gary Peltz, Zafrira Avnur, Pete Dunten

Affiliation

¹ Department of Medicinal Chemistry, Roche Palo Alto, Palo Alto, CA 94304, USA. leyi.gong@roche.com

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.

MeSH terms

Administration, Oral
Animals
Binding Sites
Crystallography, X-Ray
Disease Models, Animal
Drug Discovery
Glycogen Synthase Kinase 3 / antagonists & inhibitors*
Glycogen Synthase Kinase 3 / metabolism
Glycogen Synthase Kinase 3 beta
Indoles / chemical synthesis
Indoles / chemistry*
Indoles / pharmacokinetics
Maleimides / chemical synthesis
Maleimides / chemistry*
Maleimides / pharmacokinetics
Mice
Protein Kinase C / metabolism
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Rats
Structure-Activity Relationship

Substances

Indoles
Maleimides
Protein Kinase Inhibitors
Glycogen Synthase Kinase 3 beta
Gsk3b protein, mouse
Gsk3b protein, rat
Protein Kinase C
Glycogen Synthase Kinase 3