title: 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 11 -hydroxysteroid dehydrogenase type 1, in cynomolgus monkeys.
abstract: Glucocorticoids, through activation of the glucocorticoid receptor (GR), regulate hepatic gluconeogenesis. Elevated hepatic expression and activity of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) 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 11betaHSD1 might be a therapeutic approach to treat the metabolic syndrome. We have identified a potent 11betaHSD1 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 11betaHSD1-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 11betaHSD1 inhibitors to treat diabetes and other related metabolic diseases.
authors.affiliation: Diabetes and Metabolism Pharmacology, Genomics Institute of the Novartis Foundation, 10675 John Jay Hopkins Dr., San Diego, CA 92121, USA. gbhat@gnf.org
authors.forename: B Ganesh
authors.initials: BG
authors.lastname: Bhat
authors.forename: Natilie
authors.initials: N
authors.lastname: Hosea
authors.forename: Andrea
authors.initials: A
authors.lastname: Fanjul
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Herrera
authors.forename: Justin
authors.initials: J
authors.lastname: Chapman
authors.forename: Fred
authors.initials: F
authors.lastname: Thalacker
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stewart
authors.forename: Paul A
authors.initials: PA
authors.lastname: Rejto
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000631:Aminopyridines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002460:Cell Line; D002478:Cells, Cultured; D003348:Cortisone / Q000097:blood / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000378:metabolism; D007328:Insulin / Q000097:blood; D008252:Macaca fascicularis; D008297:Male; D011239:Prednisolone / Q000097:blood; D011241:Prednisone / Q000097:blood*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D014162:Transfection
chemical_list: C525872:4'-cyanobiphenyl-4-sulfonic acid (6-aminopyridin-2-yl)amide; D000631:Aminopyridines; D015415:Biomarkers; D007328:Insulin; D013449:Sulfonamides; D011239:Prednisolone; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C069767:phosphoenolpyruvate carboxylase kinase; D017346:Protein Serine-Threonine Kinases; D003348:Cortisone; D011241:Prednisone; D006854:Hydrocortisone