PF-915275 is a potent, selective and orally active human 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) inhibitor with a Ki of 2.3 nM and an EC50 of 15 nM (in HEK293 cells). The dose-dependent effect of PF-915275 on conversion of cortisone to cortisol in primary human and monkey hepatocytes, with an EC50 of 20 and 100 nM, respectively[1][2][3].
PF-915275 is a potent inhibitor of 11βHSD1 (in vitro HEK293, EC50 of 15 nM) in this human 11βHSD1 overexpressed cell line when coincubated in the presence of 300 nM enzyme substrate. Consistent with the species differences between human and rodent observed in biochemical assays, PF-915275 is a poor inhibitor of 11βHSD1 in rat FAO hepatoma cells, with an EC50 of 14,500 nM. PF-915275 demonstrates species-dependent potency for inhibiting cellular conversion of cortisone to cortisol in dog, monkey, and human in primary hepatocytes, with activity in human hepatocytes/monkey hepatocytes/dog hepatocytes. PF-915275 does not significantly inhibit 11βHSD2 (only 1.5% inhibition when tested at 10 μM). The dose-dependent effect of PF-915275 on conversion of cortisone to cortisol in primary human and monkey hepatocytes, with an EC50 of 20 and 100 nM, respectively[1].
The inhibition of either cortisone or prednisone turnover with PF-915275 yields similar EC50 values to that in human hepatocytes (EC50 by PF-915275 is 18 and 13 nM using cortisone and prednisone substrates, respectively) in vivo 11βHSD1 activity[1].PF-915275 dose-dependently inhibits 11βHSD1-mediated conversion of prednisone to prednisolone. A maximum of 87% inhibition is observed, with the highest tested dose of 3 mg/kg[1].The half-life of PF-915275 is 22 hours in monkey[1].PF-915275 (0.1-3 mg/kg; oral administration; for 8 hours; male cynomolgus monkeys) treatment shows a trend in dose-dependent lowering of fed plasma insulin after 8 h of dosing in these monkeys. Plasma insulin levels are significantly lowered (by 54 and 60%, respectively) at 1 and 3 mg/kg PF-915275 treatment. Plasma glucose or lipid levels are not altered with treatment[1].
References:
[1]. Bhat BG, et al. 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. J Pharmacol Exp Ther. 2008 Jan;324(1):299-305.
[2]. Siu M, et al. N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275. Bioorg Med Chem Lett. 2009 Jul 1;19(13):3493-7.
[3]. Courtney R, et al. Modulation of 11beta-hydroxysteroid dehydrogenase (11betaHSD) activity biomarkers and pharmacokinetics of PF-00915275, a selective 11betaHSD1 inhibitor. J Clin Endocrinol Metab. 2008 Feb;93(2):550-6.