JNJ-1661010

JNJ-1661010, a piperazinyl phenyl urea with its structure distinct from alkylcarbamic acid esters and α–ketoheterocyclic compounds, is a potent and selective inhibitor of fatty acid amide hydrolase (FAAH) that covalently binds to the active site of FAAH through cleavage of the urea functionality generating aniline and a FAAH-poperazinyl carbamate. The inhibition of JNJ-1661010 against FAAH is reversible through the hydrolysis of the carbamate leading to the release of the piperazinyl fragment and the restoration of enzymatic functionality of FAAH. According to results of previous studies, JNJ-1661010 displays its inhibition against recombinant FAAH with values of 50% inhibition concentration IC₅₀ of 10 nM and 12 nM in rat and human respectively.

Reference

Karbarz MJ, Luo L, Chang L, Tham CS, Palmer JA, Wilson SJ, Wennerholm ML, Brown SM, Scott BP, Apodaca RL, Keith JM, Wu J, Breitenbucher JG, Chaplan SR, Webb M. Biochemical and biological properties of 4-(3-phenyl-[1,2,4] thiadiazol-5-yl)-piperazine-1-carboxylic acid phenylamide, a mechanism-based inhibitor of fatty acid amide hydrolase. Anesth Analg. 2009;108(1):316-329.

Biochemical and biological properties of 4-(3-phenyl-[1,2,4] thiadiazol-5-yl)-piperazine-1-carboxylic acid phenylamide, a mechanism-based inhibitor of fatty acid amide hydrolase.[Pubmed:19095868]

Anesth Analg. 2009 Jan;108(1):316-29.

Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme within the amidase-signature family. It catalyzes the hydrolysis of several endogenous biologically active lipids, including anandamide (arachidonoyl ethanolamide), oleoyl ethanolamide, and palmitoyl ethanolamide. These endogenous FAAH substrates have been shown to be involved in a variety of physiological and pathological processes, including synaptic regulation, regulation of sleep and feeding, locomotor activity, pain and inflammation. Here we describe the biochemical and biological properties of a potent and selective FAAH inhibitor, 4-(3-phenyl-[1,2,4]thiadiazol-5-yl)-piperazine-1-carboxylic acid phenylamide (JNJ-1661010). The time-dependence of apparent IC(50) values at rat and human recombinant FAAH, dialysis and mass spectrometry data indicate that the acyl piperazinyl fragment of JNJ-1661010 forms a covalent bond with the enzyme. This bond is slowly hydrolyzed, with release of the piperazinyl fragment and recovery of enzyme activity. The lack of inhibition observed in a rat liver esterase assay suggests that JNJ-1661010 is not a general esterase inhibitor. JNJ-1661010 is >100-fold preferentially selective for FAAH-1 when compared to FAAH-2. JNJ-1661010 dose-dependently increases arachidonoyl ethanolamide, oleoyl ethanolamide, and palmitoyl ethanolamide in the rat brain. The compound attenuates tactile allodynia in the rat mild thermal injury model of acute tissue damage and in the rat spinal nerve ligation (Chung) model of neuropathic pain. JNJ-1661010 also diminishes thermal hyperalgesia in the inflammatory rat carrageenan paw model. These data suggest that FAAH inhibitors with modes of action similar to JNJ-1661010 may be useful clinically as broad-spectrum analgesics.

Thiadiazolopiperazinyl ureas as inhibitors of fatty acid amide hydrolase.[Pubmed:18693015]

Bioorg Med Chem Lett. 2008 Sep 1;18(17):4838-43.

A series of thiadiazolopiperazinyl aryl urea fatty acid amide hydrolase (FAAH) inhibitors is described. The molecules were found to inhibit the enzyme by acting as mechanism-based substrates, forming a covalent bond with Ser241. SAR and PK properties are presented.

JNJ-1661010 (Takeda-25) a potent and selective fatty acid amide hydrolase (FAAH) inhibitor with IC50s of 34 and 33 nM for rat FAAH and human FAAH, respectively. JNJ-1661010 can cross the blood-brain barrier and used as broad-spectrum analgesics.

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