title: Discovery libraries targeting the major enzyme classes: the serine hydrolases.
abstract: Two libraries of modestly reactive ureas containing either electron-deficient acyl anilines or acyl pyrazoles were prepared and are reported as screening libraries for candidate serine hydrolase inhibitors. Within each library is a small but powerful subset of compounds that serve as a chemotype fragment screening library capable of subsequent structural diversification. Elaboration of the pyrazole-based ureas provided remarkably potent irreversible inhibitors of fatty acid amide hydrolase (FAAH, apparent Ki=100-200 pM) complementary to those previously disclosed enlisting electron-deficient aniline-based ureas.
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla CA 92037, United States.
authors.forename: Katerina
authors.initials: K
authors.lastname: Otrubova
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla CA 92037, United States.
authors.forename: Venkat
authors.initials: V
authors.lastname: Srinivasan
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla CA 92037, United States. Electronic address: boger@scripps.edu.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D057057:Serine Proteases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D015842:Serine Proteinase Inhibitors; D054852:Small Molecule Libraries; D057057:Serine Proteases
keywords: Enzyme inhibitors; Fatty acid amide hydrolase; Screening library; Serine hydrolase inhibitors