Abstract
Glucocorticoids, through activation of the glucocorticoid receptor (GR), regulate hepatic gluconeogenesis. Elevated hepatic expression and activity of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) play a key role in ligand-induced activation of the GR through the production of cortisol. Evidence from genetically modified mice suggests that inhibition of 11βHSD1 might be a therapeutic approach to treat the metabolic syndrome. We have identified a potent 11βHSD1 inhibitor, 4′-cyano-biphenyl-4-sulfonic acid (6-amino-pyridin-2-yl)-amide (PF-915275), that is selective for the primate and human enzymes. The objective of this study was to demonstrate target inhibition with PF-915275 and to quantify the relationship between target inhibition and drug exposure in monkeys. We characterized the ability of PF-915275 to inhibit the conversion of prednisone, a synthetic cortisone analog that can be distinguished from the endogenous substrate cortisone, enabling a direct measure of substrate to product conversion without the complication of feedback. Adult cynomolgus monkeys were administered either vehicle or various doses of PF-915275 followed by a 10-mg/kg dose of prednisone. Prednisone conversion to prednisolone and the concentrations of PF-915275 were measured by liquid chromatography/tandem mass spectrometry. PF-915275 dose-dependently inhibited 11βHSD1-mediated conversion of prednisone to prednisolone, with a maximum of 87% inhibition at a 3-mg/kg dose. An exposure-response relationship was demonstrated, with an estimated EC50 of 391 nM (total) and 17 nM (free). Insulin levels were also reduced in a dose-related manner. These results should enable the development of a biomarker for evaluating target modulation in humans that will aid in identifying 11βHSD1 inhibitors to treat diabetes and other related metabolic diseases.
Footnotes
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B.G.B. and N.H. contributed equally to this work.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.128280.
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ABBREVIATIONS: 11βHSD1, 11β-hydroxysteroid dehydrogenase type 1; 11βHSD2, 11β-hydroxysteroid dehydrogenase type 2; PEPCK, phosphoenolpyruvate carboxykinase; PF-915275, 4′-cyano-biphenyl-4-sulfonic acid (6-amino-pyridin-2-yl)-amide; HEK, human embryonic kidney; DMEM, Dulbecco's modified Eagle's medium; EIA, enzyme immunoassay; LC/MS/MS, liquid chromatography/tandem mass spectrometry; AUC, area under the curve; PCR, polymerase chain reaction; GR, glucocorticoid receptor; GRE, glucocorticoid response element(s); E, cortisone; F, cortisol.
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↵1 Current affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
- Received August 20, 2007.
- Accepted October 2, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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