Design of Selective, ATP-Competitive Inhibitors of Akt

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 analogu...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2010-06, Vol.53 (12), p.4615-4622
Main Authors: Freeman-Cook, Kevin D, Autry, Christopher, Borzillo, Gary, Gordon, Deborah, Barbacci-Tobin, Elsa, Bernardo, Vincent, Briere, David, Clark, Tracey, Corbett, Matthew, Jakubczak, John, Kakar, Shefali, Knauth, Elizabeth, Lippa, Blaise, Luzzio, Michael J, Mansour, Mahmoud, Martinelli, Gary, Marx, Matthew, Nelson, Kendra, Pandit, Jayvardhan, Rajamohan, Francis, Robinson, Shaughnessy, Subramanyam, Chakrapani, Wei, Liuqing, Wythes, Martin, Morris, Joel
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - physiology
Amides - chemical synthesis
Amides - pharmacokinetics
Amides - pharmacology
Aminoquinolines - chemical synthesis
Aminoquinolines - pharmacokinetics
Aminoquinolines - pharmacology
Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Crystallography, X-Ray
Dogs
Mice
Models, Molecular
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - pharmacokinetics
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
Rats
Stereoisomerism
Structure-Activity Relationship
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm1003842