Discovery of potent and selective PKC-theta inhibitors.
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.
Cywin
Charles L
CL
Boehringer Ingelheim Pharmaceuticals, Inc., Department of Medicinal Chemistry, 900 Ridgebury Road, Ridgefield, CT 06877-0368, USA. ccywin@rdg.boehringer-ingelheim.com
Dahmann
Georg
G
Prokopowicz
Anthony S
AS
Young
Erick R R
ER
Magolda
Ronald L
RL
Cardozo
Mario G
MG
Cogan
Derek A
DA
Disalvo
Darren
D
Ginn
John D
JD
Kashem
Mohammed A
MA
Wolak
John P
JP
Homon
Carol A
CA
Farrell
Thomas M
TM
Grbic
Heather
H
Hu
Hanbo
H
Kaplita
Paul V
PV
Liu
Lisa H
LH
Spero
Denice M
DM
Jeanfavre
Deborah D
DD
O'Shea
Kathy M
KM
White
Della M
DM
Woska
Joseph R
JR
Brown
Maryanne L
ML
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
D007376:Interleukin-2; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta