RT Journal Article
SR Electronic
T1 Demonstration of Proof of Mechanism and Pharmacokinetics and Pharmacodynamic Relationship with 4′-Cyano-biphenyl-4-sulfonic Acid (6-Amino-pyridin-2-yl)-amide (PF-915275), an Inhibitor of 11β-Hydroxysteroid Dehydrogenase Type 1, in Cynomolgus Monkeys
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 299
OP 305
DO 10.1124/jpet.107.128280
VO 324
IS 1
A1 B. Ganesh Bhat
A1 Natilie Hosea
A1 Andrea Fanjul
A1 Jocelyn Herrera
A1 Justin Chapman
A1 Fred Thalacker
A1 Paul M. Stewart
A1 Paul A. Rejto
YR 2008
UL http://jpet.aspetjournals.org/content/324/1/299.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics