@article {492,
	title = {Switching reversibility to irreversibility in glycogen synthase kinase 3 inhibitors: clues for specific design of new compounds},
	journal = {Journal of medicinal chemistry},
	volume = {54},
	year = {2011},
	month = {2011/06/23/},
	pages = {4042 - 4056},
	abstract = {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 IC(50) 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.},
	keywords = {Adenosine Triphosphate/chemistry; Animals; Binding Sites; Cattle; Central Nervous System Agents/chemical synthesis/chemistry/pharmacology; Cerebellum/cytology; Drug Design; Glycogen Synthase Kinase 3/antagonists \& inhibitors; Humans; Ketones/chemical synt, Molecular; Neurodegenerative Diseases/drug therapy; Neurons/drug effects/metabolism; Phosphorylation; Protein Binding; Rats; Receptors, Neurotransmitter/antagonists \& inhibitors; Stereoisomerism; Structure-Activity Relationship; tau Proteins/metabolism},
	author = {Perez,D. I. and Palomo,V. and Perez,C. and Gil,C. and Dans,P. D. and F. J. Luque and Conde,S. and Martinez,A.}
}
