2. Academic Validation
  3. Design of selective, ATP-competitive inhibitors of Akt

Design of selective, ATP-competitive inhibitors of Akt

  • J Med Chem. 2010 Jun 24;53(12):4615-22. doi: 10.1021/jm1003842.
Kevin D Freeman-Cook 1,  Christopher Autry,  Gary Borzillo,  Deborah Gordon,  Elsa Barbacci-Tobin,  Vincent Bernardo,  David Briere,  Tracey Clark,  Matthew Corbett,  John Jakubczak,  Shefali Kakar,  Elizabeth Knauth,  Blaise Lippa,  Michael J Luzzio,  Mahmoud Mansour,  Gary Martinelli,  Matthew Marx,  Kendra Nelson,  Jayvardhan Pandit,  Francis Rajamohan,  Shaughnessy Robinson,  Chakrapani Subramanyam,  Liuqing Wei,  Martin Wythes,  Joel Morris
Affiliations

Affiliation

  • 1 Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA. kevin.freeman-cook@pfizer.com
PMID: 20481595 DOI: 10.1021/jm1003842
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-10721
    ≥98.0%, Akt 抑制剂
    Akt
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