Discovery of Novel GSK-3β Inhibitors with Excellent Brain Permeability
Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana 71201, United States
J. Med. Chem., 2010, 53 (24), pp 8534–8545
DOI: 10.1021/jm100941j
Publication Date (Web): November 17, 2010
Copyright © 2010 American Chemical Society
*To whom correspondence should be addressed. Phone: +1 318 342 1725. Fax: +1 318 342 1737. E-mail: elsayed@ulm.edu.
Abstract
Dysregulation of glycogen synthase kinase (GSK-3β) is implicated in the pathophysiology of many diseases, including type-2 diabetes, stroke, Alzheimer’s, and others. A multistage virtual screening strategy designed so as to overcome known caveats arising from the considerable flexibility of GSK-3β yielded, from among compounds in our in-house database and two commercial databases, new GSK-3β inhibitors with novel scaffold structures. The two most potent and selective validated hits, a 2-anilino-5-phenyl-1,3,4-oxadiazole (24) and a phenylmethylene hydantoin (28), both exhibited nanomolar affinity and selectivity over CDK2 and were potent enough for direct in vivo validation. Both were able to cause significant increases in liver glycogen accumulation in dose-dependent fashion. One also exhibited excellent blood−brain barrier permeability, the other adequate for a lead compound. Analogues of the oxadiazole 24 were synthesized to experimentally corroborate or rule out ligand-bound structures arising from docking studies. SAR results supported one docking study among a number of alternatives.
Supporting Information
Analytical data of compounds 1, 4, 6, 8, 13, 16, 17, 19, 21, 23, 24, 27, 28, 30, and GSK-3β inhibitory activity graphs of 24 and 28. This material is available free of charge via the Internet at http://pubs.acs.org.
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