1. Novel bis(indolyl)maleimide pyridinophanes that are potent, selective inhibitors of glycogen synthase kinase-3.
- Author
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Zhang HC, Boñaga LV, Ye H, Derian CK, Damiano BP, and Maryanoff BE
- Subjects
- Adenosine Triphosphate metabolism, Binding Sites, Drug Design, Enzyme Inhibitors chemical synthesis, Glycogen Synthase Kinase 3 chemistry, Glycogen Synthase Kinase 3 beta, Hydrophobic and Hydrophilic Interactions, Maleimides chemistry, Models, Molecular, Molecular Structure, Protein Conformation, Pyridines chemistry, Structure-Activity Relationship, Enzyme Inhibitors pharmacology, Glycogen Synthase Kinase 3 antagonists & inhibitors, Pyridines pharmacology
- Abstract
Novel bis(indolyl)maleimide pyridinophanes 3, 9a, 9b, 10a, 10b, and 11 were prepared by cobalt-mediated [2+2+2] cycloaddition of an appropriate alpha,omega-diyne with an N,N-dialkylcyanamide. These macrocyclic heterophanes were found to be potent, selective inhibitors of glycogen synthase kinase-3beta. An X-ray structure of a co-crystal of GSK-3beta and 3 (IC(50)=3nM) depicts the hydrogen bonding and hydrophobic interactions in the ATP-binding pocket of this serine/threonine protein kinase.
- Published
- 2007
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