Design of Selective, ATP-Competitive Inhibitors of Akt

被引：63

作者：

Freeman-Cook, Kevin D. ^{[1
]}

Autry, Christopher ^{[1
]}

Borzillo, Gary ^{[1
]}

Gordon, Deborah ^{[1
]}

Barbacci-Tobin, Elsa ^{[1
]}

Bernardo, Vincent ^{[1
]}

Briere, David ^{[1
]}

Clark, Tracey ^{[1
]}

Corbett, Matthew ^{[1
]}

Jakubczak, John ^{[1
]}

Kakar, Shefali ^{[1
]}

Knauth, Elizabeth ^{[1
]}

Lippa, Blaise ^{[1
]}

Luzzio, Michael J. ^{[1
]}

Mansour, Mahmoud ^{[1
]}

Martinelli, Gary ^{[1
]}

Marx, Matthew ^{[1
]}

Nelson, Kendra ^{[1
]}

Pandit, Jayvardhan ^{[1
]}

Rajamohan, Francis ^{[1
]}

Robinson, Shaughnessy ^{[1
]}

Subramanyam, Chakrapani ^{[1
]}

Wei, Liuqing ^{[1
]}

Wythes, Martin ^{[1
]}

Morris, Joel ^{[1
]}

机构：

[1] Pfizer Inc, Global Res & Dev, Groton, CT 06340 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 12期

关键词：

PROTEIN-KINASE-B; ALLOSTERIC DUAL AKT-1; PI3K/AKT PATHWAY; SIGNALING PATHWAY; MAMMALIAN TARGET; POTENT; DISCOVERY; IDENTIFICATION; ACTIVATION; EFFICACY;

D O I：

10.1021/jm1003842

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：4615 / 4622

页数：8

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