Glucocorticoids, through activation of the glucocorticoid receptor (GR), regulate hepatic gluconeogenesis. Elevated hepatic expression and activity of 11␤-hydroxysteroid dehydrogenase type 1 (11␤HSD1) 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 11␤HSD1 might be a therapeutic approach to treat the metabolic syndrome. We have identified a potent 11␤HSD1 inhibitor, 4Ј-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 11␤HSD1-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 EC 50 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 11␤HSD1 inhibitors to treat diabetes and other related metabolic diseases.The enzyme 11␤-hydroxysteroid dehydrogenase type 1 (11␤HSD1) catalyzes the intracrine conversion of inactive cortisone to the active glucocorticoid agonist cortisol. The 11␤HSD1 knockout mouse is unable to convert inactive glucocorticoid to the active glucocorticoid, suggesting that 11␤HSD1 is the unique enzyme responsible for this conversion (Kotelevtsev et al., 1997). Emerging data suggest that the local production of cortisol within liver and adipose tissue through the action of 11␤HSD1 might represent an important advance in the pathogenesis, and more importantly, the treatment of patients with the metabolic syndrome (insulin resistance, central obesity, hypertension, hyperlipidemia) (Tomlinson and Stewart, 2005).Evidence indicating a role for 11␤HSD1 as a therapeutic approach to treat type 2 diabetes and related metabolic dis-B.G.B. and N.H. contributed equally to this work. 1

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