Discovery of potent and bioavailable GSK-3beta inhibitors.

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Gong L, Hirschfeld D, Tan YC, Heather Hogg J, Peltz G, Avnur Z, Dunten P

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.

PubMed ID

20138512 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
3-[3-(2,3-Dihydroxy-Propylamino)-Phenyl]-4-(5-Fluoro-1-Methyl-1h-Indol-3-Yl)-Pyrrole-2,5-Dione	Glycogen synthase kinase-3 beta	IC 50 (nM)	0.6	N/A	N/A	Details
3-[3-(2,3-Dihydroxy-Propylamino)-Phenyl]-4-(5-Fluoro-1-Methyl-1h-Indol-3-Yl)-Pyrrole-2,5-Dione	Glycogen synthase kinase-3 beta	Kd (nM)	0.053	N/A	N/A	Details