title: 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.
abstract: 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.
authors.affiliation: Pain and Related Disorders, Johnson and Johnson Pharmaceutical Research and Development, LLC, San Diego, California 92121, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Karbarz
authors.forename: Lin
authors.initials: L
authors.lastname: Luo
authors.forename: Leon
authors.initials: L
authors.lastname: Chang
authors.forename: Chui-Se
authors.initials: CS
authors.lastname: Tham
authors.forename: James A
authors.initials: JA
authors.lastname: Palmer
authors.forename: Sandy J
authors.initials: SJ
authors.lastname: Wilson
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Wennerholm
authors.forename: Sean M
authors.initials: SM
authors.lastname: Brown
authors.forename: Brian P
authors.initials: BP
authors.lastname: Scott
authors.forename: Richard L
authors.initials: RL
authors.lastname: Apodaca
authors.forename: John M
authors.initials: JM
authors.lastname: Keith
authors.forename: Jiejun
authors.initials: J
authors.lastname: Wu
authors.forename: James Guy
authors.initials: JG
authors.lastname: Breitenbucher
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Chaplan
authors.forename: Michael
authors.initials: M
authors.lastname: Webb
mesh_terms: D000577:Amides; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002351:Carrageenan; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004983:Ethanolamines; D006358:Hot Temperature; D006801:Humans; D006868:Hydrolysis; D007527:Isoenzymes; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009437:Neuralgia / Q000209:etiology / Q000517:prevention & control; D009829:Oleic Acids / Q000378:metabolism; D010146:Pain / Q000209:etiology / Q000517:prevention & control*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010169:Palmitic Acids / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013830:Thiadiazoles / Q000494:pharmacology*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000577:Amides; D000581:Amidohydrolases; D000700:Analgesics; D001095:Arachidonic Acids; D002351:Carrageenan; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D007527:Isoenzymes; D009829:Oleic Acids; D010169:Palmitic Acids; D010879:Piperazines; D053284:Polyunsaturated Alkamides; D011994:Recombinant Proteins; D013830:Thiadiazoles; D000099252:Fatty Acid Amide Hydrolases; C534402:4-(3-phenyl-(1,2,4)-thiadiazol-5-yl)piperazine-1-carboxylic acid phenylamide; C488250:oleoylethanolamide; C005958:palmidrol; C516565:FAAH2 protein, human; C078814:anandamide