Pharmacological properties of SD-282 - an alpha-isoform selective inhibitor for p38 MAP kinase.

The effects of small-molecule p38 inhibitors in numerous models of different disease states have been published, including those of SD-282, an indole-5-carboxamide inhibitor. The aim of the present study was to evaluate the pharmacological activity of SD-282 on cytokine production in vitro as well as in 2 in vivo models of inflammation in order to illuminate the role of this particular inhibitor in diverse disease states. The results presented here provide further characterization of SD-282 and provide a context in which to interpret the activity of this p38 inhibitor in models of arthritis, pain, myocardial injury, sepsis and asthma; all of which have an inflammatory component.

Preventive and therapeutic potential of p38 alpha-selective mitogen-activated protein kinase inhibitor in nonobese diabetic mice with type 1 diabetes.

Mitogen-activated protein kinases (MAPKs) and heat shock proteins (HSPs) are ubiquitous proteins that function within T cells in both normal and stress-related pathophysiological states, including type 1 diabetes. The nonobese diabetic (NOD) mouse spontaneously develops T cell-mediated autoimmune pancreatic beta cell destruction that is similar to type 1 diabetes in humans. Because p38 MAPKs have been shown to modulate T cell function, we studied the effects of a p38alpha MAPK-selective inhibitor, indole-5-carboxamide (SD-169), on the development and progression of type 1 diabetes in the NOD mouse.

Modeling individual variation in biomarker response to combination immunosuppression with stimulated lymphocyte responses-potential clinical implications.

Background: In mitogen-stimulated lymphocyte responses (sLR), cytokines and cell-surface receptors in peripheral human blood lymphocytes (PBL) are sensitive to cyclosporine (CsA), and can predict its in vivo effect with pharmacodynamic (PD) modeling. This is not known for multiple-agent combinations.

Methods: Twenty-five concentration mixtures of CsA (0-1200 ng/ml) plus sirolimus (SRL, 0-30 ng/ml) were added to whole blood from five normal human subjects (NHS) for effect on a limited array of six targets.