Switching Reversibility to Irreversibility in Glycogen Synthase Kinase 3 Inhibitors: Clues for Specific Design of New Compounds

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• 作者：Daniel I. Perez ; Valle Palomo ; Concepcio虂n Pe虂rez ; Carmen Gil ; Pablo D. Dans ; F. Javier Luque ; Santiago Conde ; Ana Marti虂nez
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：June 23, 2011
• 年：2011
• 卷：54
• 期：12
• 页码：4042-4056
• 全文大小：1187K
• 年卷期：v.54,no.12(June 23, 2011)
• ISSN：1520-4804

文摘

Development of kinase-targeted therapies for central nervous system (CNS) diseases is a great challenge. Glycogen synthase kinase 3 (GSK-3) offers a great potential for severe CNS unmet diseases, being one of the inhibitors on clinical trials for different tauopathies. Following our hypothesis based on the enhanced reactivity of residue Cys199 in the binding site of GSK-3, we examine here the suitability of phenylhalomethylketones as irreversible inhibitors. Our data confirm that the halomethylketone unit is essential for the inhibitory activity. Moreover, addition of the halomethylketone moiety to reversible inhibitors turned them into irreversible inhibitors with IC₅₀ values in the nanomolar range. Overall, the results point out that these compounds might be useful pharmacological tools to explore physiological and pathological processes related to signaling pathways regulated by GSK-3 opening new avenues for the discovery of novel GSK-3 inhibitors.