Glucocorticoids are widely prescribed to treat autoimmune and inflammatory diseases; however, despite their extreme potency and efficacy, their clinical utility is limited by a variety of adverse side effects. In this issue Roohk et al. use heavy water labeling and mass spectrometry to measure fluxes through disease-relevant pathways in mice and describe a novel arylpyrazole-based glucocorticoid receptor modulator, L5 [[1-(4-fluorophenyl)-4a-methyl-5, 6,7,8-tetrahydro-4H-benzo[f]indazol-5-yl]-[4-(trifluoromethyl)phenyl]methanol]. Glucocorticoid-like effects on insulin resistance, hippocampal neurogenesis, and gene expression in liver and muscle (PEPCK and Murf1, respectively) were observed with L5 but not the potentially adverse effects on bone and skin collagen synthesis or muscle protein synthesis, suggesting that L5 acts as a selective glucocorticoid receptor modulator. These studies demonstrate the novel utility of simultaneous measurement of dynamic fluxes in a wide array of target pathways as an efficient and powerful tool to interrogate phenotypic selectivity of agents in vivo.
See article at J Pharmacol Exp Ther 2010, 333:281–289.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics