title: Heteroaryl urea inhibitors of fatty acid amide hydrolase: structure-mutagenicity relationships for arylamine metabolites.
abstract: The structure-activity relationships for a series of heteroaryl urea inhibitors of fatty acid amide hydrolase (FAAH) are described. Members of this class of inhibitors have been shown to inactivate FAAH by covalent modification of an active site serine with subsequent release of an aromatic amine from the urea electrophile. Systematic Ames II testing guided the optimization of urea substituents by defining the structure-mutagenicity relationships for the released aromatic amine metabolites. Potent FAAH inhibitors were identified having heteroaryl amine leaving groups that were non-mutagenic in the Ames II assay.
authors.affiliation: Janssen Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States. mticheno@its.jnj.com
authors.forename: Mark S
authors.initials: MS
authors.lastname: Tichenor
authors.forename: John M
authors.initials: JM
authors.lastname: Keith
authors.forename: William M
authors.initials: WM
authors.lastname: Jones
authors.forename: Joan M
authors.initials: JM
authors.lastname: Pierce
authors.forename: Jeff
authors.initials: J
authors.lastname: Merit
authors.forename: Natalie
authors.initials: N
authors.lastname: Hawryluk
authors.forename: Mark
authors.initials: M
authors.lastname: Seierstad
authors.forename: James A
authors.initials: JA
authors.lastname: Palmer
authors.forename: Michael
authors.initials: M
authors.lastname: Webb
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Karbarz
authors.forename: Sandy J
authors.initials: SJ
authors.lastname: Wilson
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Wennerholm
authors.forename: Filip
authors.initials: F
authors.lastname: Woestenborghs
authors.forename: Dominiek
authors.initials: D
authors.lastname: Beerens
authors.forename: Lin
authors.initials: L
authors.lastname: Luo
authors.forename: Sean M
authors.initials: SM
authors.lastname: Brown
authors.forename: Marlies De
authors.initials: MD
authors.lastname: Boeck
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Chaplan
authors.forename: J Guy
authors.initials: JG
authors.lastname: Breitenbucher
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000588:Amines / Q000378:metabolism*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000588:Amines; D004791:Enzyme Inhibitors; D006899:Mixed Function Oxygenases; D009153:Mutagens; D014508:Urea; D000099252:Fatty Acid Amide Hydrolases; C035198:arylamine N-hydroxylase