PF-915275

PF-915275 is a potent, selective and orally active human 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) inhibitor with a K_i 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]. IC50 & Target: Ki: 2.3 nM (11βHSD1); EC50: 15 nM (11βHSD1)^[1] In Vitro: 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]. In Vivo: 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].