Discovery of bicyclic pyrazoles as class III histone deacetylase SIRT1 and SIRT2 inhibitors

[Display omitted] A series of bicyclic pyrazole carboxamides was synthesized and tested for inhibitory activity against the class III deacetylase sirtuin enzymes. Moderate to low micromolar inhibitory activities were obtained against SIRT1 and SIRT2. These bicyclic pyrazole compounds represent a new...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2015-06, Vol.25 (12), p.2514-2518
Hauptverfasser:	Therrien, Eric, Larouche, Guillaume, Nguyen, Natalie, Rahil, Jubrail, Lemieux, Anne-Marie, Li, Zuomei, Fournel, Marielle, Yan, Theresa P., Landry, Anne-Julie, Lefebvre, Sylvain, Wang, James J., MacBeth, Kyle, Heise, Carla, Nguyen, Aaron, Besterman, Jeffrey M., Déziel, Robert, Wahhab, Amal
Format:	Artikel
Sprache:	eng
Schlagworte:	Binding Sites Bridged Bicyclo Compounds - chemistry Catalytic Domain Crystallography, X-Ray Docking Drug Evaluation, Preclinical Inhibitor Molecular Dynamics Simulation Protein Binding Pyrazole Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - metabolism SIRT Sirtuin Sirtuin 1 - antagonists & inhibitors Sirtuin 1 - metabolism Sirtuin 2 - antagonists & inhibitors Sirtuin 2 - metabolism Structure-Activity Relationship
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Zusammenfassung:	[Display omitted] A series of bicyclic pyrazole carboxamides was synthesized and tested for inhibitory activity against the class III deacetylase sirtuin enzymes. Moderate to low micromolar inhibitory activities were obtained against SIRT1 and SIRT2. These bicyclic pyrazole compounds represent a new class of sirtuin inhibitors with a preference for SIRT1 over SIRT2.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2015.04.068