PF-04457845 is a greatly and effctive FAAH inhibitor, and for hFAAH(IC50=7.2±0.63 nM) and rFAAH(IC50=7.4±0.62 nM).

FAAH (human):7.2±0.63 nM, FAAH (rat):7.4±0.62 nM

PF-04457845通过共价、不可逆的机制抑制FAAH，该机制涉及FAAH活性位点丝氨酸核苷酸的氨基甲酸化，具有高体外活性（针对人类FAAH的kinact/Ki和IC50值分别为40300 M^-1s^-1和7.2 nM）。

在大鼠模型中，口服PF-04457845后，通过4小时的观察发现，以最小有效剂量（MED）0.1 mg/kg显著抑制了机械痛觉过敏。在以PF-04457845（1及10 mg/kg p.o.）处理的小鼠中，FAAH活性被完全抑制。

The IC50 values for the inhibition of hFAAH and rFAAH by PF-04457845 is determined. PF-04457845 is preincubated with FAAH for 60 min before initiating the reaction by the addition of the substrate oleamide. Mouse and human tissues are prepared and inhibitor selectivity is assessed by competitive activity-based protein profiling.

PF-04457845 is formulated as a nanocrystalline suspension in 2% polyvinylpyrrolidone and 0.15% sodium dodecyl sulfate in H2O (Rats). PF-04457845 is prepared in polyethyleneglycol 300 (Mice).RatsPF-04457845 is administered orally to male Sprague-Dawley rats (200 g-250 g) at the indicated dose (mg/kg) as a nanocrystalline suspension in 2% polyvinylpyrrolidone and 0.15% sodium dodecyl sulfate in H2O. The dose volume is 10 mL/kg. The Paw Withdrawal Threshold (PWT) is evaluated at 4 h post dose. PWT measurements are averaged and statistical comparisons between groups are made using analysis of variance and unpaired T-tests.Mice Male C57BL6/J mice (7 weeks old; n=8) are treated with PF-04457845 (1 or 10 mg/kg in polyethyleneglycol 300 vehicle by oral administration in a volume of 4 mL/kg), the synthetic cannabinoid agonist WIN 55,212-2 (1 or 10 mg/kg in 18:1:1 saline/Emulphor/ethanol vehicle by intraperitoneal administration in a volume of 10 mL/kg), or the corresponding vehicle. Mice are evaluated for hypomotility, hypothermia, antinociceptive, and cataleptic effects at 4 h or 30 min after PF-04457845 or WIN 55,212-2 administration, respectively, using the tetrad tests except that catalepsy is assessed for 60 s instead of 10 s. Statistical analysis is performed using the Student's t test comparing each treatment group with vehicle.

Male C57BL6/J mice (7 weeks old) are treated with PF-04457845 (1 or 10 mg/kg in polyethyleneglycol 300 vehicle by oral administration in a volume of 4 mL/kg).