PF-3845

PF-3845, the piperidine urea covalent inhibitor of fatty acid amide hydrolase (FAAH; EC 3.5.1.99), was disclosed in 2009 by a collaborative team at Pfizer Global Research and Development (Groton, Connecticut) and The Scripps Research Institute (La Jolla, California) as a highly selective tool compound for interrogating the endocannabinoid system in vivo. The compound carbamylates the catalytic serine nucleophile (Ser241) of FAAH with a kinact/Ki of 14,310 M-1 s-1 and a Ki of 0.23 micromolar, producing irreversible enzyme inactivation that is sustained for greater than 24 hours in mouse brain after a single oral dose. Unlike the earlier carbamate FAAH inhibitor URB597, PF-3845 demonstrates exquisite selectivity for FAAH across the broader serine hydrolase superfamily as assessed by competitive activity-based protein profiling (ABPP), showing no detectable inhibition of liver carboxylesterases, FAAH-2, or other off-target serine hydrolases at pharmacologically relevant concentrations. Administration of PF-3845 to rodents produces rapid and sustained elevation of brain anandamide (AEA), N-palmitoyl ethanolamine (PEA), and N-oleoyl ethanolamine (OEA) levels by approximately 10-fold without altering 2-arachidonoylglycerol (2-AG) concentrations, consistent with selective FAAH blockade rather than monoacylglycerol lipase (MAGL) inhibition.

The preclinical pharmacology of PF-3845 spans inflammatory and neuropathic pain, traumatic brain injury, anxiety, acute stress, gastrointestinal inflammation, and bone resorption. In the complete Freund's adjuvant (CFA) rat model of inflammatory pain, oral PF-3845 at 10 mg/kg produced antinociceptive efficacy comparable to naproxen at 10 mg/kg, with the effect dependent on both CB1 and CB2 cannabinoid receptor activation. In mouse models of traumatic brain injury, chronic post-injury treatment with PF-3845 reversed impairments in fine motor movement, hippocampus-dependent working memory, and anxiety-like behavior while reducing neurodegeneration, suppressing proinflammatory markers, and promoting a shift from M1 to M2 microglial phenotype. The compound produces rapid and sustained anxiolytic effects in rodents exposed to acute stress or chronic corticosterone, reverses lipopolysaccharide-induced tactile allodynia through neuronal mechanisms, attenuates hippocampal neuroinflammation following acute restraint stress, displays antidiarrheal and anti-inflammatory activity in mouse colitis models, and suppresses osteoclastogenesis through ERK and NF-kappaB pathway inhibition in vitro and in vivo.

PF-3845 served as the direct synthetic precursor to PF-04457845, the clinical-candidate FAAH inhibitor that Pfizer advanced through Phase 2 human trials for osteoarthritis pain and cannabis use disorder. The medicinal chemistry optimization from PF-3845 to PF-04457845 involved conformational constraint of the piperidine ring and replacement of the 3-aminopyridine leaving group with a pyridazine, yielding approximately 3-fold improvement in kinact/Ki against human FAAH, a 30-fold reduction in minimum effective dose in the CFA pain model (from 3 mg/kg to 0.1 mg/kg), and improved pharmaceutical properties suitable for once-daily oral dosing. PF-3845 itself has not entered human clinical trials and remains a preclinical research tool, but its pharmacological profile and the extensive literature built upon it (greater than 100 citations in the primary research literature) establish it as one of the most thoroughly characterized selective FAAH inhibitors available to investigators. The compound is supplied by multiple research chemical vendors at greater than 98 percent purity and is soluble to 100 mM in dimethyl sulfoxide. This monograph reviews the chemistry, covalent mechanism, selectivity, pharmacokinetics, preclinical pharmacology across pain, neuroinflammation, anxiety, gastrointestinal, and bone indications, sourcing and handling, stack interactions, adverse-event signal, and a comparative assessment of five FAAH inhibitor candidates against PF-3845 on five competency standards.