PF-915275 is an effective and selective inhibitor of human 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1, Ki = 2.3 nM, EC50 = 15 nM in vitro 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.

11β-HSD1:15 nM(EC50), 11β-HSD1:2.3 nM(Ki)

PF-915275 is a poor inhibitor of 11βHSD1 in rat FAO hepatoma cells (EC50: 14,500 nM), consistent with the species differences between humans and rodents observed in biochemical assays. 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. PF-915275 does not significantly inhibit 11βHSD2 (only 1.5% inhibition when tested at 10 μM). PF-915275 shows species-dependent potency for inhibiting the cellular conversion of cortisone to cortisol in a dog, monkey, and human in primary hepatocytes, with activity in human hepatocytes/monkey hepatocytes/dog hepatocytes [1].

PF-915275 dose-dependently inhibits the 11βHSD1-mediated conversion of prednisone to prednisolone. A maximum of 87% inhibition is observed, with the highest tested dose of 3 mg/kg. 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. The half-life of PF-915275 is 22 hours in the monkey. 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. PF-915275 (0.1-3 mg/kg; p.o.; for 8 hours; male cynomolgus monkeys) treatment displays a trend in dose-dependent lowering of fed plasma insulin after 8 h of dosing in these monkeys [1].