5-Vinyl-3-pyridinecarbonitrile inhibitors of PKCθ: Optimization of enzymatic and functional activity

Abstract PKCθ 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 PKCθ. 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 Log  D 7.4 , but not with c  Log  P , PAMPA permeability, or TPSA.