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

Abstract

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

11β-Hydroxysteroid dehydrogenase type 1 regulates insulin and glucagon secretion in pancreatic islets

“…Selective 11β-HSD1 inhibitors decrease local glucocorticoid generation in rodent and primate models and in humans [39][40][41]. To date, clinical efficacy has only been demonstrated in rodents, which showed improved glucose tolerance and lipid profiles, as well as increased insulin sensitivity and decreased atherogenesis [42,43].…”

11β-Hydroxysteroid Dehydrogenase Type 1 and the Metabolic Syndrome

“…So far, to our knowledge, there are no reports of PF-915275 activity in patients with T2DM or MetSyn (or any of the associated components). Bhat et al showed, in normal cynomolgus monkeys, that PF-915275 dose-dependently inhibits 11 -HSD1-mediated conversion of prednisone to prednisolone and reduces insulin levels (Bhat et al, 2008). Hollis et al reviewed the clinical results obtained with the selective 11 -HSD1 inhibitor INCB13739.…”

“…11 -HSD2 is expressed principally in the distal nephron, where it inactivates cortisol to cortisone and thereby protects MR from cortisol (Andrews et al, 2003;Edwards et al, 1988;Ferrari, 2010;Funder et al, 1988;Palermo et al, 2004). PF-915275 is a potent and selective 11 -HSD1 inhibitor, without adverse side effects in a wide range of orally tested doses, that is selective for the human and primate enzymes (Bhat et al, 2008;Courtney et al, 2008). A modest pharmacodynamic effect of PF-915275 on 11 -HSD1 activity in the healthy human liver is reported, but experiments to assess its inhibitory effect in the AT have not been performed (Courtney et al, 2008;Hollis & Huber, 2011).…”

“…Several and distinct selective 11 -HSD1 inhibitors are being produced, developed and tested in vitro, ex vivo and in vivo, in normal animals, rodent models of metabolic alterations or disease (hyperglycemia, dyslipidemia, atherosclerosis, IR, T2DM, obesity, diet-induced obesity and/or MetSyn) and some of them already in humans, healthy or not (Alberts et al, 2002;Alberts et al, 2003;Barf et al, 2002;Bhat et al, 2008;Bujalska et al, 2008a;Cho et al, 2009;Cooper & Stewart, 2009;Coppola et al, 2005;Courtney et al, 2008;Feig et al, 2011;Gathercole & Stewart, 2010;Ge et al, 2010;Hermanowski-Vosatka et al, 2005;Hollis & Huber, 2011;Hughes et al, 2008;Hult et al, 2006;Johansson et al, 2008;Julian et al, 2008;J. Liu et al, 2011;Morgan et al, 2009;Morgan & Tomlinson, 2010;Morton, 2010;Park et al, 2011;Rosenstock et al, 2010;U.…”

Discovery of 2-Alkyl-1-arylsulfonylprolinamides as 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors

“…5 Some clinical candidates, such as INCB-13739 and PF-915275, lack potency against rodent enzyme, so in vivo pharmacokinetics (PK)/PD studies of these compounds require primate models. 16 In our series, cross-species potencies of adamant-2-yl derivatives 4d and 4e allowed us to employ rodent model.…”