title: Discovery of potent and selective PKC-theta inhibitors.
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.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Department of Medicinal Chemistry, 900 Ridgebury Road, Ridgefield, CT 06877-0368, USA. ccywin@rdg.boehringer-ingelheim.com
authors.forename: Charles L
authors.initials: CL
authors.lastname: Cywin
authors.forename: Georg
authors.initials: G
authors.lastname: Dahmann
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Prokopowicz
authors.forename: Erick R R
authors.initials: ER
authors.lastname: Young
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Magolda
authors.forename: Mario G
authors.initials: MG
authors.lastname: Cardozo
authors.forename: Derek A
authors.initials: DA
authors.lastname: Cogan
authors.forename: Darren
authors.initials: D
authors.lastname: Disalvo
authors.forename: John D
authors.initials: JD
authors.lastname: Ginn
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Kashem
authors.forename: John P
authors.initials: JP
authors.lastname: Wolak
authors.forename: Carol A
authors.initials: CA
authors.lastname: Homon
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Farrell
authors.forename: Heather
authors.initials: H
authors.lastname: Grbic
authors.forename: Hanbo
authors.initials: H
authors.lastname: Hu
authors.forename: Paul V
authors.initials: PV
authors.lastname: Kaplita
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Liu
authors.forename: Denice M
authors.initials: DM
authors.lastname: Spero
authors.forename: Deborah D
authors.initials: DD
authors.lastname: Jeanfavre
authors.forename: Kathy M
authors.initials: KM
authors.lastname: O'Shea
authors.forename: Della M
authors.initials: DM
authors.lastname: White
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Woska
authors.forename: Maryanne L
authors.initials: ML
authors.lastname: Brown
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D000074121:Protein Kinase C-theta; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D007376:Interleukin-2; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta