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, 6 (12), 1204-8

Preclinical Characterization of the FAAH Inhibitor JNJ-42165279


Preclinical Characterization of the FAAH Inhibitor JNJ-42165279

John M Keith et al. ACS Med Chem Lett.


The pre-clinical characterization of the aryl piperazinyl urea inhibitor of fatty acid amide hydrolase (FAAH) JNJ-42165279 is described. JNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channels, transporters, and receptors. JNJ-42165279 exhibited excellent ADME and pharmacodynamic properties as evidenced by its ability to block FAAH in the brain and periphery of rats and thereby cause an elevation of the concentrations of anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA). The compound was also efficacious in the spinal nerve ligation (SNL) model of neuropathic pain. The combination of good physical, ADME, and PD properties of JNJ-42165279 supported it entering the clinical portfolio.

Keywords: FAAH; anandamide; covalent; enzyme; ethanolamides.

Conflict of interest statement

The authors declare no competing financial interest.


Figure 1
Figure 1
Some known FAAH inhibitors.
Scheme 1
Scheme 1. Synthesis of JNJ-42165279
Conditions: (a) 4 equiv of piperazine, 18 h; (b) two cycles through an H-Cube 20% Pd(OH)2/C, 1 atm. H2 (10% excess), 70 °C, 6 mL/min, 83%; (c) 0.95 equiv of PhOCOCl, 1.20 equiv of pyridine, toluene, 2–5 °C, 7 h; (d) 1.0 equiv of 1, 1.5 equiv of K2CO3, water, 15 h, recrystallized from hot i-PrOAc, 50% over two steps.
Figure 2
Figure 2
Proposed biotransformation scheme for JNJ-42165279 in mouse, rat, dog, monkey, and human. For metabolites not found in all species, the species of metabolite detection is denoted in parentheses. Ms, mouse; R, rat; D, dog; Mk, monkey; H, human. The locations at which biotransformations occurred was narrowed through the use of a MS–MS analysis of secondary ions. The boxed area is where the biotransformation took place.
Figure 3
Figure 3
Efficacy of JNJ-42165279 in the rat SNL model of neuropathic pain. The data are expressed as the percentage of the maximum possible effect (%MPE). Top graph: JNJ-42165279 dose-dependently decreased the tactile allodynia associated with this model. The ED90 in this model was determined to be 22 mg/kg, which corresponds to a plasma concentration of 2.5 M at the 30 min time point. Bottom graph: the time course of the antiallodynic efficacy of JNJ-42165279 (60 mg/kg p.o.) in the SNL model.

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