Abstract
This paper describes the design and synthesis of novel, ATP-competitive Akt inhibitors from an elaborated 3-aminopyrrolidine scaffold. Key findings include the discovery of an initial lead that was modestly selective and medicinal chemistry optimization of that lead to provide more selective analogues. Analysis of the data suggested that highly lipophilic analogues would likely suffer from poor overall properties. Central to the discussion is the concept of optimization of lipophilic efficiency and the ability to balance overall druglike propeties with the careful control of lipophilicity in the lead series. Discovery of the nonracemic amide series and subsequent modification produced an advanced analogue that performed well in advanced preclinical assays, including xenograft tumor growth inhibition studies, and this analogue was nominated for clinical development.
MeSH terms
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Adenosine Triphosphate / physiology*
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Amides / chemical synthesis*
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Amides / pharmacokinetics
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Amides / pharmacology
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Aminoquinolines / chemical synthesis*
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Aminoquinolines / pharmacokinetics
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Aminoquinolines / pharmacology
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Crystallography, X-Ray
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Dogs
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Mice
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Models, Molecular
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
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Rats
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Stereoisomerism
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Amides
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Aminoquinolines
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Adenosine Triphosphate
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Proto-Oncogene Proteins c-akt
Associated data
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PDB/3MV5
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PDB/3MVH
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PDB/3MVJ