Abstract
PKCtheta is a serine/threonine kinase involved in the regulation of IL2 production in T cells. It has recently become an attractive therapeutic target for a variety of immunological disorders. We describe the optimization of the enzymatic and cellular potency of a series of 5-vinyl-3-pyridinecarbonitrile inhibitors of PKCtheta. A binding model was developed that explains much of the SAR observed for this series, including the enzymatic potency observed for 19. An analysis of functional potency against various physiochemical parameters suggests that cellular potency is correlated with LogD(7.4), but not with cLogP, PAMPA permeability, or TPSA.
MeSH terms
-
Animals
-
Computer Simulation
-
Inhibitory Concentration 50
-
Isoenzymes / antagonists & inhibitors*
-
Isoenzymes / metabolism
-
Kinetics
-
Magnetic Resonance Spectroscopy
-
Mice
-
Mice, Inbred C57BL
-
Models, Molecular
-
Nitriles / chemical synthesis*
-
Nitriles / chemistry
-
Nitriles / pharmacology
-
Protein Kinase C / antagonists & inhibitors*
-
Protein Kinase C / metabolism
-
Protein Kinase C-theta
-
Protein Kinase Inhibitors / chemical synthesis*
-
Protein Kinase Inhibitors / chemistry
-
Protein Kinase Inhibitors / pharmacology
-
Pyridines / chemical synthesis*
-
Pyridines / chemistry
-
Pyridines / pharmacology
-
Spectrometry, Mass, Electrospray Ionization
-
Structure-Activity Relationship
-
Vinyl Compounds / chemical synthesis*
-
Vinyl Compounds / chemistry
-
Vinyl Compounds / pharmacology
Substances
-
Isoenzymes
-
Nitriles
-
Protein Kinase Inhibitors
-
Pyridines
-
Vinyl Compounds
-
Prkcq protein, mouse
-
Protein Kinase C
-
Protein Kinase C-theta