Novel inhibitors of fatty acid amide hydrolase.
A class of bisarylimidazole derivatives are identified as potent inhibitors of the enzyme fatty acid amide hydrolase (FAAH). Compound 17 (IC(50)=2 nM) dose-dependently (0.1-10mg/kg, iv) potentiates the effects of exogenous anandamide (1 mg/kg, iv) in a rat thermal escape test (Hargreaves test), and shows robust antinociceptive activity in animal models of persistent (formalin test) and neuropathic (Chung model) pain. Compound 17 (20 mg/kg, iv) demonstrates activity in the formalin test that is comparable to morphine (3mg/kg, iv), and is dose-dependently inhibited by the CB1 antagonist SR141716A. In the Chung model, compound 17 shows antineuropathic effects similar to high-dose (100 mg/kg) gabapentin. FAAH inhibition shows potential utility for the clinical treatment of persistent and neuropathic pain.
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Department of Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492-7660, USA. singyuen.sit@bms.com
Conway
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Bertekap
Robert
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Xie
Kai
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Bourin
Clotilde
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Burris
Kevin
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Deng
Hongfeng
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D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000588:Amines / Q000494:pharmacology; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000077206:Gabapentin; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D010880:Piperidines / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077285:Rimonabant; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D004791:Enzyme Inhibitors; D000077206:Gabapentin; D007093:Imidazoles; D009020:Morphine; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant; D005680:gamma-Aminobutyric Acid; D000099252:Fatty Acid Amide Hydrolases