"目录号: HY-14376
Metabolic Enzyme/ProteaseNeuronal 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。
FAAH
相关产品
BIA 10-2474-LY2183240-URB-597-PF-3845-JNJ-42165279-JZL195-FAAH-IN-2-Biochanin A-FAAH inhibitor 1-
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
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Yale University-Tourette Association of America
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May 2014
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Yale University
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May 2012
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Yale University-National Institute on Drug Abuse (NIDA)
Cannabis Dependence
June 2012
Phase 2
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References
[1].Johnson DS, et al. Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor. ACS Med Chem Lett. 2011 Feb 10;2(2):91-96.
[2].Ahn K, et al. Mechanistic and pharmacological characterization of PF-04457845: a highly potent and selective fatty acid amide hydrolase inhibitor that reduces inflammatory and noninflammatory pain. J Pharmacol Exp Ther. 2011 Jul;338(1):114-24.
[3].Buntyn RW, et al. Inhibition of Endocannabinoid-Metabolizing Enzymes in Peripheral Tissues Following Developmental Chlorpyrifos Exposure in Rats. Int J Toxicol. 2017 Jan 1:1091581817725272.