The inhibitory effect of PF-915275 on cortisone or prednisone conversion is similar to the EC50 value of human hepatocytes (18 nM and 13 nM respectively when using cortisone and prednisone substrates) in vivo 11βHSD1 activity ^[1].

Furthermore, PF-915275's inhibition of the conversion from cortisone to cortisol, and similarly from prednisone to prednisolone, in human hepatocytes is dose-dependent, achieving up to 87% inhibition at the highest tested dose of 3 mg/kg^[1].

PF-915275 also exhibits a trend towards dose-dependent reduction of plasma insulin levels following oral administration (0.1-3 mg/kg for 8 hours) in male cynomolgus monkeys, significantly reducing insulin levels by 54% and 60% at 1 mg/kg and 3 mg/kg, respectively, without altering plasma glucose or lipid levels^[1].

PF-915275 shows a high level of efficacy in inhibiting 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in a human cell line overexpressing the enzyme (HEK293), with an EC50 of 15 nM in the presence of a 300 nM enzyme substrate. This potency contrasts sharply with its performance in rat FAO hepatoma cells, where it is much less effective, with an EC50 value of 14,500 nM, highlighting significant species-specific variations in its inhibitory action. This species-dependent effectiveness is also observed in primary hepatocytes from dogs, monkeys, and humans, with PF-915275 exhibiting activity across these species, but most potently in humans. Notably, PF-915275 has minimal impact on 11βHSD2, showing only 1.5% inhibition at a concentration of 10 μM, indicating its selectivity for 11βHSD1.