TY - JOUR T1 - Differential <em>in vivo</em> effects on target pathways of a novel arylpyrazole glucocorticoid receptor modulator compared to prednisolone JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.109.162487 SP - jpet.109.162487 AU - Donald J. Roohk AU - Krista A. Varady AU - Scott M. Turner AU - Claire L. Emson AU - Richard W. Gelling AU - Mahalakshmi Shankaran AU - Glen Lindwall AU - Lauren E. Shipp AU - Thomas S. Scanlan AU - Jen-Chywan Wang AU - Marc K. Hellerstein Y1 - 2010/01/01 UR - http://jpet.aspetjournals.org/content/early/2010/01/20/jpet.109.162487.abstract N2 - Glucocorticoids are widely prescribed to treat autoimmune and inflammatory diseases. While they are extremely potent, their utility in clinical practice is limited by a variety of adverse side effects. Development of compounds that retain the potent immunomodulating and anti-inflammatory properties of classic glucocorticoids while exhibiting reduced adverse actions is therefore a priority. Using heavy water labeling and mass-spectrometry to measure fluxes through multiple glucocorticoid-responsive disease-relevant target pathways in vivo in mice, we compared the effects of a classic glucocorticoid receptor ligand, prednisolone, to those of a novel arylpyrazole-based compound, L5. We show for the first time that L5 exhibits clearly selective actions on disease-relevant pathways compared to prednisolone. Prednisolone reduced bone collagen synthesis, skin collagen synthesis, muscle protein synthesis, and splenic lymphocyte counts, proliferation, and cell death, whereas L5 had none of these actions. In contrast, L5 was a more rapid and potent inhibitor of hippocampal neurogenesis than was prednisolone; and L5 and prednisolone induced insulin resistance equally. Administration of prednisolone or L5 increased expression comparably for one GR-regulated gene involved in protein degradation in skeletal muscle (Murf1) and one GR-regulated gluconeogenic gene in liver (PEPCK). In summary, L5 dissociates the pleiotropic effects of the GR ligand prednisolone in intact animals in ways that neither gene expression nor cell-based models were able to fully capture or predict. Because multiple actions can be measured concurrently in a single animal, this method is a powerful systems approach for characterizing and differentiating the effects of ligands that bind nuclear receptors.The American Society for Pharmacology and Experimental Therapeutics ER -