Optimization of 2,3,5-trisubstituted pyridine derivatives as potent allosteric Akt1 and Akt2 inhibitors

This letter shows inhibitor SAR on a pyridine series of allosteric Akt inhibitors to optimize enzymatic and cellular potency. We have optimized 2,3,5-trisubstituted pyridines to give potent Akt1 and Akt2 inhibitors in both enzyme and cell based assays. In addition, we will also highlight the pharmac...

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Veröffentlicht in:	Bioorganic & medicinal chemistry 2008-03, Vol.18 (6), p.2194-2197
Hauptverfasser:	Hartnett, John C., Barnett, Stanley F., Bilodeau, Mark T., Defeo-Jones, Deborah, Hartman, George D., Huber, Hans E., Jones, Raymond E., Kral, Astrid M., Robinson, Ronald G., Wu, Zhicai
Format:	Artikel
Sprache:	eng
Schlagworte:	Akt1 Akt2 Allosteric Site Animals Apoptosis - drug effects Caspases - metabolism Cellular Dogs Enzymatic Humans Inhibitors Male Metabolic Clearance Rate Molecular Structure Prostatic Neoplasms - drug therapy Prostatic Neoplasms - metabolism Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins c-akt - antagonists & inhibitors Proto-Oncogene Proteins c-akt - metabolism Pyridines - chemistry Structure-Activity Relationship TNF-Related Apoptosis-Inducing Ligand - pharmacology Tumor Cells, Cultured
Online-Zugang:	Volltext
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Beschreibung
Zusammenfassung:	This letter shows inhibitor SAR on a pyridine series of allosteric Akt inhibitors to optimize enzymatic and cellular potency. We have optimized 2,3,5-trisubstituted pyridines to give potent Akt1 and Akt2 inhibitors in both enzyme and cell based assays. In addition, we will also highlight the pharmacokinetic profile of an optimized inhibitor that has low clearance and long half-life in dogs.
ISSN:	0960-894X 0968-0896 1464-3405 1464-3391
DOI:	10.1016/j.bmcl.2007.12.040