1. Metabolic Enzyme/Protease
    Neuronal Signaling
  2. FAAH

PF-04457845 (Synonyms: PF 04457845; PF04457845)

Cat. No.: HY-14376 Purity: 98.20%
Data Sheet SDS Handling Instructions

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.

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PF-04457845 Chemical Structure

PF-04457845 Chemical Structure

CAS No. : 1020315-31-4

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10 mM * 1 mL in DMSO $77 In-stock
5 mg $70 In-stock
10 mg $110 In-stock
25 mg $220 In-stock
50 mg $400 In-stock
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  • Biological Activity

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  • Technical Information

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Description

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 (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 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
NCT Number Sponsor Condition Start Date Phase
NCT01002625 Pfizer Sleep|Healthy Volunteers November 2009 Phase 1
NCT00981357 Pfizer Osteoarthritis, Knee November 2009 Phase 2
NCT01092845 Pfizer Healthy|Sleep April 2010 Phase 1
NCT00918164 Pfizer Healthy Volunteers May 2009 Phase 1
NCT02216097 Pfizer Post-Traumatic Stress Disorder October 2014 Phase 2
NCT00836082 Pfizer Acute Pain|Chronic Pain February 2009 Phase 1
NCT02134080 Yale University|Tourette Association of America Tourette Syndrome May 2014 Phase 2
NCT01665573 Yale University Fear Conditioning May 2012 Phase 2
NCT01618656 Yale University|National Institute on Drug Abuse (NIDA) Cannabis Dependence June 2012 Phase 2
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References
Preparing Stock Solutions
Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
1 mM 2.1957 mL 10.9786 mL 21.9573 mL
5 mM 0.4391 mL 2.1957 mL 4.3915 mL
10 mM 0.2196 mL 1.0979 mL 2.1957 mL
Kinase Assay
[1]

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[1].

Animal Administration
[1][2]

PF-04457845 is formulated as a nanocrystalline suspension in 2% polyvinylpyrrolidone and 0.15% sodium dodecyl sulfate in H2O (Rat)[1].
PF-04457845 is prepared in polyethyleneglycol 300 (Mice)[2].

Rat[1]
PF-04457845 is administered orally to male Sprague-Dawley rats (200g-250g) 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[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 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.

References
M.Wt

455.43

Formula

C₂₃H₂₀F₃N₅O₂

CAS No.

1020315-31-4

Storage

Please store the product under the recommended conditions in the Certificate of Analysis.

Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

10 mM in DMSO

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

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PF-04457845
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