PF-04457845_DataSheet_MedChemExpress

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Data Sheet

Product Name:Cat. No.:CAS No.:

Molecular Formula:Molecular Weight:Target:Pathway:Solubility:

PF–04457845HY-143761020315-31-4C23H20F3N5O2455.43FAAH; FAAH

Neuronal Signaling; Metabolic Enzyme/Protease10 mM in DMSO

BIOLOGICAL ACTIVITY: 

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 andrFAAH, 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/Ki 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 bycompetitive activity–based protein profiling. PF–04457845 completely inhibits FAAH in human and mouse membrane proteomes atboth 10 and 100 μM with no off targets[1]. PF–04457845 is completely selective for FAAH, and none of the other FP–reactive serinehydrolases 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 measuredafter 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 painresponse to a comparable degree as the nonsteroidal anti–inflammatory drug naproxen at 10 mg/kg[1]. FAAH is confirmed to becompletely inhibited in mice treated with PF–04457845 at 1 and 10 mg/kg p.o. by competitive activity–based protein profiling(ABPP) study[2].

PROTOCOL (Extracted from published papers and Only for reference)

Kinase Assay:[1]The IC50 values for the inhibition of hFAAH and rFAAH by PF–04457845 is determined. PF–04457845 ispreincubated with FAAH for 60 min before initiating the reaction by the addition of the substrate oleamide. Mouse and humantissues are prepared and inhibitor selectivity is assessed by competitive activity–based protein profiling[1].dodecyl sulfate in H2O (Rat)[1].

Animal Administration: PF–04457845 is formulated as a nanocrystalline suspension in 2% polyvinylpyrrolidone and 0.15% sodiumPF–04457845 is prepared in polyethyleneglycol 300 (Mice)[2].[1][2]Rat[1]

PF–04457845 is administered orally to male Sprague–Dawley rats (200g–250g) at the indicated dose (mg/kg) as a nanocrystallinesuspension in 2% polyvinylpyrrolidone and 0.15% sodium dodecyl sulfate in H2O. The dose volume is 10 mL/kg. The Paw WithdrawalThreshold (PWT) is evaluated at 4 h post dose. PWT measurements are averaged and statistical comparisons between groups aremade using analysis of variance and unpaired T–tests.Mice[2]

Male C57BL6/J mice (7 weeks old; n=8) are treated with PF–04457845 (1 or 10 mg/kg in polyethyleneglycol 300 vehicle by oraladministration 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

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evaluated for hypomotility, hypothermia, antinociceptive, and cataleptic effects at 4 h or 30 min after PF–04457845 or WIN 55,212–2administration, respectively, using the tetrad tests except that catalepsy is assessed for 60 s instead of 10 s. Statistical analysis isperformed using the Student's t test comparing each treatment group with vehicle.

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 thatreduces inflammatory and noninflammatory pain. J Pharmacol Exp Ther. 2011 Jul;338(1):114–24.

Caution: Product has not been fully validated for medical applications. For research use only.

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