Identification and optimization of indolo[2,3-c]quinoline inhibitors of IRAK4.

IRAK4 is responsible for initiating signaling from Toll-like receptors (TLRs) and members of the IL-1/18 receptor family. Kinase-inactive knock-ins and targeted deletions of IRAK4 in mice cause reductions in TLR induced pro-inflammatory cytokines and these mice are resistant to various models of arthritis. Herein we report the identification and optimization of a series of potent IRAK4 inhibitors.

Osteogenic effects of a potent Src-over-Abl-selective kinase inhibitor in the mouse.

Src-null mice have higher bone mass because of decreased bone resorption and increased bone formation, whereas Abl-null mice are osteopenic, because of decreased bone formation. Compound I, a potent inhibitor of Src in an isolated enzyme assay (IC(50) 0.55 nM) and a Src-dependent cell growth assay, with lower activity on equivalent Abl-based assays, potently, but biphasically, accelerated differentiation of human mesenchymal stem cells to an osteoblast phenotype (1-10 nM).

Optimization of 7-alkene-3-quinolinecarbonitriles as Src kinase inhibitors.

The 7-alkene-3-quinolinecarbonitrile 20, a potent inhibitor of Src enzymatic and cellular activity with IC(50) values of 2.1 and 58 nM, respectively, had comparable efficacy to bosutinib in a colon tumor xenograft study.

Optimization of 5-vinylaryl-3-pyridinecarbonitriles as PKCtheta inhibitors.

Analog 8, a 3-pyridinecarbonitrile with an (E)-2-[6-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl]vinyl group at C-5, had an IC(50) value of 1.1 nM for the inhibition of PKCtheta and potently blocked the production of IL-2 in both stimulated murine T cells (IC(50)=34 nM) and human whole blood (IC(50)=500 nM).

5-Vinyl-3-pyridinecarbonitrile inhibitors of PKCtheta: optimization of enzymatic and functional activity.

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.