Abstract
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.
MeSH terms
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Allosteric Site*
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Animals
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Apoptosis / drug effects
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Caspases / metabolism
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Dogs
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Humans
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Male
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Metabolic Clearance Rate
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Molecular Structure
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / metabolism
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
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Proto-Oncogene Proteins c-akt / metabolism
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Pyridines / chemistry*
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Structure-Activity Relationship
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TNF-Related Apoptosis-Inducing Ligand / pharmacology
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Tumor Cells, Cultured
Substances
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Protein Kinase Inhibitors
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Pyridines
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Proto-Oncogene Proteins c-akt
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Caspases
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pyridine