RESEARCH MONOGRAPH · KDC-MN-329

PF-04457845

May 9, 2026 Kodiac biolabs Research Revised May 30, 2026 3 min read

Our opinion on this compound

73/100

Best-in-class FAAH inhibitor, clean clinical data, useful research tool even though Pfizer shelved it

PF-04457845 is what URB597 wants to be when it grows up. Pfizer designed it as a clinical-stage FAAH inhibitor, the medicinal chemistry is tighter (urea-based covalent mechanism, much better selectivity over off-target serine hydrolases), the PK is meaningfully better, and unlike URB597 it actually went through human Phase 1 and 2 trials with reasonable safety data.

Mechanism: covalent FAAH inhibitor, sub-nanomolar IC50, selectivity over MAGL and other off-targets is excellent (several orders of magnitude), oral bioavailability is good, half-life supports daily dosing. Brain penetration is solid, demonstrated 95%+ FAAH inhibition in human CSF in the Huggins et al phase 1 work.

Clinical record is mixed in informative ways. The osteoarthritis pain trial (the Huggins paper) failed to beat placebo, which was a meaningful negative signal for FAAH inhibition as a generic analgesic strategy. But the cannabis withdrawal trial (D'Souza et al, Lancet Psychiatry 2019) was positive: PF-04457845 reduced cannabis use and withdrawal symptoms in dependent users. Thats actually a really clean clinical signal for endocannabinoid system pharmacology.

The compound also acquired a complicated reputation because of the Bial BIA 10-2474 disaster in 2016, where a different FAAH inhibitor caused a death in a phase 1 trial in France. That was almost certainly off-target toxicity from BIA 10-2474's poor selectivity, not a FAAH-mediated effect, but it cast a shadow over the whole class for a while. PF-04457845's clean selectivity profile is part of why it survived that period.

For research it's a markedly better tool than URB597 when you can get it. Cleaner pharmacology, less off-target noise, better PK for chronic in vivo work. The downside is it's harder to source at quality and meaningfully more expensive per gram than URB597.

Sourcing: research-grade material is available from specialized suppliers, HPLC/LCMS verification is essential, the urea chemistry is sensitive enough that some lots have degradant issues. Worth getting a fresh CoA.

What we like: clean mechanism, good PK, real human clinical data (positive and negative both informative), best-in-class FAAH tool for serious in vivo work.

What we dont like: cost, sourcing inconsistency for high-purity material, the orphan-program status means no new clinical development is happening.

If you're doing FAAH-target research seriously, this is the compound you want.

Evidence: 78
Mechanism: 88
Reliability: 80
Safety: 78
Sourcing: 65
Value: 55
Signal: 72
Staying power: 70

Plain-language summary Intrigue 64 / 100

PF-04457845 is the most thoroughly studied FAAH inhibitor in humans, developed by Pfizer to raise endogenous anandamide as a non-cannabinoid approach to pain and anxiety. Phase 1 and 2 trials in osteoarthritis and fibromyalgia produced disappointing efficacy, and the compound is best remembered for its association with the 2016 Bial trial disaster in France, where a different FAAH inhibitor (BIA 10-2474) caused one death and severe neurological injury in five healthy volunteers. Subsequent investigation found the Bial compound had broad off-target lipase activity that PF-04457845 lacks, and the FAAH approach itself was not implicated. PF-04457845 is now being studied for cannabis use disorder. Not stocked by Kodiac. This monograph is provided for research and educational reference.

Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

Selective FAAH inhibitor (clinical-stage)

A clinical-stage FAAH inhibitor; the most thoroughly studied FAAH inhibitor in human trials, including a tragic phase 1 fatality at Bial.

Abstract

PF-04457845 (CAS 1020315-31-4; molecular formula C20H21F3N4O3; molecular weight 422.40) is a covalent piperidine-urea FAAH inhibitor developed at Pfizer. The compound is selective for FAAH over other serine hydrolases and produces elevated plasma and brain N-acylethanolamides (anandamide, OEA, PEA) at clinical doses. Phase 1 and 2 clinical trials in osteoarthritis pain, fibromyalgia, and (more recently) cannabis use disorder have demonstrated FAAH target engagement and modest clinical effects in some indications. The compound is most associated with the broader FAAH inhibitor scrutiny following the 2016 Bial Pharmaceuticals tragedy in Rennes, where a different FAAH inhibitor (BIA-10-2474) caused one death and severe neurological injury in a phase 1 trial; the cause was attributed to off-target effects unique to BIA-10-2474, exonerating PF-04457845 specifically. Plasma half-life is approximately 14 hours. Used as the canonical clinical-stage FAAH inhibitor for translational research.

Mechanism of action

Covalent FAAH inhibitor; selective for FAAH over other serine hydrolases. Elevates anandamide, OEA, and PEA in plasma and brain.

Reported research dose ranges

Trial doses 1 to 4 mg in the published literature.

References

Huggins JP, et al. An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845 in osteoarthritic knee pain. Pain 2012.
D'Souza DC, et al. Efficacy and safety of a fatty acid amide hydrolase inhibitor (PF-04457845) in the treatment of cannabis withdrawal and dependence. Lancet Psychiatry 2019.
Kerbrat A, et al. Acute neurologic disorder from an inhibitor of fatty acid amide hydrolase. N Engl J Med 2016.

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KDC-MN-329

The full reference document is provided strictly for research use only. It reports research dose ranges from the published literature, not instructions for use in humans or animals.

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FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

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PF-04457845

Abstract

Mechanism of action

Reported research dose ranges

References

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Abstract

Mechanism of action

Reported research dose ranges

References

Read the full monograph

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