title: Structure-activity relationships of alpha-ketooxazole inhibitors of fatty acid amide hydrolase.
abstract: A systematic study of the structure-activity relationships of 2b (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed targeting the C2 acyl side chain. A series of aryl replacements or substituents for the terminal phenyl group provided effective inhibitors (e.g., 5c, aryl = 1-napthyl, Ki = 2.6 nM), with 5hh (aryl = 3-ClPh, Ki = 900 pM) being 5-fold more potent than 2b. Conformationally restricted C2 side chains were examined, and many provided exceptionally potent inhibitors, of which 11j (ethylbiphenyl side chain) was established to be a 750 pM inhibitor. A systematic series of heteroatoms (O, NMe, S), electron-withdrawing groups (SO, SO2), and amides positioned within and hydroxyl substitutions on the linking side chain were investigated, which typically led to a loss in potency. The most tolerant positions provided effective inhibitors (12p, 6-position S, Ki = 3 nM, or 13d, 2-position OH, Ki = 8 nM) comparable in potency to 2b. Proteome-wide screening of selected inhibitors from the systematic series of >100 candidates prepared revealed that they are selective for FAAH over all other mammalian serine proteases.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hardouin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kelso
authors.forename: F Anthony
authors.initials: FA
authors.lastname: Romero
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rayl
authors.forename: Donmienne
authors.initials: D
authors.lastname: Leung
authors.forename: Inkyu
authors.initials: I
authors.lastname: Hwang
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D010080:Oxazoles / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D010080:Oxazoles; D000099252:Fatty Acid Amide Hydrolases