PF-04457845

"目录号: HY-14376

Metabolic Enzyme/Protease Neuronal Signaling-

PF-04457845 是一种高效选择性的FAAH抑制剂，作用于hFAAH和rFAAH，IC50分别为 7.2±0.63 nM 和 7.4±0.62 nM。

生物活性

Description

PF-04457845 is a highly efficacious and selectiveFAAHinhibitor withIC50values is 7.2±0.63 nM and 7.4±0.62 nM forhFAAHandrFAAH, 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 (kinact/Kiand IC50values of 40300 M-1s-1and 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 μM 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 μM[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].

Clinical Trial

NCT01002625

Pfizer

Sleep-Healthy Volunteers

November 2009

Phase 1

NCT00981357

Pfizer

Osteoarthritis, Knee

November 2009

Phase 2

NCT01092845