PF-04457845

1020315-31-4

455.43

DMSO : >= 100 mg/mL (219.57 mM)

Neuronal Signaling; Metabolic Enzyme/Protease; Autophagy

PF-04457845 is a highly efficacious and selective FAAH inhibitor with IC₅₀ values is 7.2+/-0.63 nM and 7.4+/-0.62 nM for hFAAH and rFAAH, respectively. IC50 & Target: IC50: 7.2+/-0.63 nM (hFAAH), 7.4+/-0.62 nM (rFAAH)^[1] In Vitro: PF-04457845 inhibits FAAH by a covalent, irreversible mechanism involving carbamylation of the active-site serine nucleophile of FAAH with high in vitro potency (k_inact/K_i and IC₅₀ values of 40300 M^-1s^-1 and 7.2 nM, respectively, for human FAAH). PF-04457845 has exquisite selectivity for FAAH relative to other members of the serine hydrolase superfamily as demonstrated by competitive activity-based protein profiling. PF-04457845 completely inhibits FAAH in human and mouse membrane proteomes at both 10 and 100 uM with no off targets^[1]. PF-04457845 is completely selective for FAAH, and none of the other FP-reactive serine hydrolases in the tested tissues are inhibited by PF-04457845 even at 100 uM^[2]. In Vivo: Oral administration of PF-04457845 at 0.1 mg/kg results in efficacy comparable to that of naproxen at 10 mg/kg in a rat model of inflammatory pain. Oral administration of PF-04457845 causes a significant inhibition of mechanical allodynia measured after 4 h with a minimum effective dose (MED) of 0.1 mg/kg. Furthermore, at 0.1 mg/kg (p.o.), PF-04457845 inhibits the pain response to a comparable degree as the nonsteroidal anti-inflammatory drug naproxen at 10 mg/kg^[1]. FAAH is confirmed to be completely inhibited in mice treated with PF-04457845 at 1 and 10 mg/kg p.o. by competitive activity-based protein profiling (ABPP) study^[2].