Discovery of potent and selective PKC-theta inhibitors

  • Bioorg Med Chem Lett. 2007 Jan 1;17(1):225-30. doi: 10.1016/j.bmcl.2006.09.056.
Charles L Cywin  1 ,  Georg Dahmann ,  Anthony S Prokopowicz 3rd ,  Erick R R Young ,  Ronald L Magolda ,  Mario G Cardozo ,  Derek A Cogan ,  Darren Disalvo ,  John D Ginn ,  Mohammed A Kashem ,  John P Wolak ,  Carol A Homon ,  Thomas M Farrell ,  Heather Grbic ,  Hanbo Hu ,  Paul V Kaplita ,  Lisa H Liu ,  Denice M Spero ,  Deborah D Jeanfavre ,  Kathy M O'Shea ,  Della M White ,  Joseph R Woska Jr ,  Maryanne L Brown
Affiliations
  • 1. Boehringer Ingelheim Pharmaceuticals, Inc., Department of Medicinal Chemistry, 900 Ridgebury Road, Ridgefield, CT 06877-0368, USA. [email protected]
PMID: 17055721 DOI: 10.1016/j.bmcl.2006.09.056
Abstract

An uHTS campaign was performed to identify selective inhibitors of PKC-theta. Initial triaging of the hit set based on selectivity and historical analysis led to the identification of 2,4-diamino-5-nitropyrimidines as potent and selective PKC-theta inhibitors. A homology model and initial SAR is presented demonstrating that a 2-arylalkylamino substituent in conjunction with suitable 4-diamino substituent are essential for achieving selectivity over many kinases. Additional hit to lead profiling is presented on selected compounds.

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