title: Benzothiophene piperazine and piperidine urea inhibitors of fatty acid amide hydrolase (FAAH).
abstract: The synthesis and structure-activity relationships (SAR) of a series of benzothiophene piperazine and piperidine urea FAAH inhibitors is described. These compounds inhibit FAAH by covalently modifying the enzyme's active site serine nucleophile. Activity-based protein profiling (ABPP) revealed that these urea inhibitors were completely selective for FAAH relative to other mammalian serine hydrolases. Several compounds showed in vivo activity in a rat complete Freund's adjuvant (CFA) model of inflammatory pain.
authors.affiliation: Pfizer Global Research and Development, Ann Arbor, MI 48105, USA. doug.johnson@pfizer.com
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Johnson
authors.forename: Kay
authors.initials: K
authors.lastname: Ahn
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kesten
authors.forename: Scott E
authors.initials: SE
authors.lastname: Lazerwith
authors.forename: Yuntao
authors.initials: Y
authors.lastname: Song
authors.forename: Mark
authors.initials: M
authors.lastname: Morris
authors.forename: Lorraine
authors.initials: L
authors.lastname: Fay
authors.forename: Tracy
authors.initials: T
authors.lastname: Gregory
authors.forename: Cory
authors.initials: C
authors.lastname: Stiff
authors.forename: James B
authors.initials: JB
authors.lastname: Dunbar
authors.forename: Marya
authors.initials: M
authors.lastname: Liimatta
authors.forename: David
authors.initials: D
authors.lastname: Beidler
authors.forename: Sarah
authors.initials: S
authors.lastname: Smith
authors.forename: Tyzoon K
authors.initials: TK
authors.lastname: Nomanbhoy
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008956:Models, Chemical; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D010879:Piperazines; D010880:Piperidines; D013876:Thiophenes; D014508:Urea; D000099252:Fatty Acid Amide Hydrolases; C088015:benzothiophene