Differential in vivo effects on target pathways of a novel arylpyrazole glucocorticoid receptor modulator compared with prednisolone

Donald J. Roohk, Krista A. Varady, Scott M. Turner, Claire L. Emson, Richard W. Gelling, Mahalakshmi Shankaran, Glen Lindwall, Lauren E. Shipp, Thomas (Tom) Scanlan, Jen Chywan Wang, Marc K. Hellerstein

Research output: Contribution to journalArticle

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Abstract

Glucocorticoids are widely prescribed to treat autoimmune and inflammatory diseases. Although 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 (GR) ligand, prednisolone, with those of a novel arylpyrazole-based compound, L5 {[1-(4-fluorophenyl)-4a-methyl-5,6,7,8-tetrahydro-4H-benzo-[f]indazol-5-yl] -[4-(trifluoromethyl)phenyl]methanol}. We show for the first time that L5 exhibits clearly selective actions on disease-relevant pathways compared with 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 those actions. In contrast, L5 was a more rapid and potent inhibitor of hippocampal neurogenesis than 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.

Original languageEnglish (US)
Pages (from-to)281-289
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume333
Issue number1
DOIs
StatePublished - Apr 2010

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Glucocorticoid Receptors
Prednisolone
Glucocorticoids
Ligands
Collagen
Deuterium Oxide
Muscle Proteins
Neurogenesis
Lymphocyte Count
Cytoplasmic and Nuclear Receptors
Systems Analysis
Proteolysis
Genes
Autoimmune Diseases
Insulin Resistance
Mass Spectrometry
Skeletal Muscle
Cell Death
Anti-Inflammatory Agents
Gene Expression

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Differential in vivo effects on target pathways of a novel arylpyrazole glucocorticoid receptor modulator compared with prednisolone. / Roohk, Donald J.; Varady, Krista A.; Turner, Scott M.; Emson, Claire L.; Gelling, Richard W.; Shankaran, Mahalakshmi; Lindwall, Glen; Shipp, Lauren E.; Scanlan, Thomas (Tom); Wang, Jen Chywan; Hellerstein, Marc K.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 333, No. 1, 04.2010, p. 281-289.

Research output: Contribution to journalArticle

Roohk, DJ, Varady, KA, Turner, SM, Emson, CL, Gelling, RW, Shankaran, M, Lindwall, G, Shipp, LE, Scanlan, TT, Wang, JC & Hellerstein, MK 2010, 'Differential in vivo effects on target pathways of a novel arylpyrazole glucocorticoid receptor modulator compared with prednisolone', Journal of Pharmacology and Experimental Therapeutics, vol. 333, no. 1, pp. 281-289. https://doi.org/10.1124/jpet.109.162487
Roohk, Donald J. ; Varady, Krista A. ; Turner, Scott M. ; Emson, Claire L. ; Gelling, Richard W. ; Shankaran, Mahalakshmi ; Lindwall, Glen ; Shipp, Lauren E. ; Scanlan, Thomas (Tom) ; Wang, Jen Chywan ; Hellerstein, Marc K. / Differential in vivo effects on target pathways of a novel arylpyrazole glucocorticoid receptor modulator compared with prednisolone. In: Journal of Pharmacology and Experimental Therapeutics. 2010 ; Vol. 333, No. 1. pp. 281-289.
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