title: O-(triazolyl)methyl carbamates as a novel and potent class of fatty acid amide hydrolase (FAAH) inhibitors.
abstract: Inhibition of fatty acid amide hydrolase (FAAH) activity is under investigation as a valuable strategy for the treatment of several disorders, including pain and drug addiction. A number of potent FAAH inhibitors belonging to different chemical classes have been disclosed to date; O-aryl carbamates are one of the most representative families. In the search for novel FAAH inhibitors, a series of O-(1,2,3-triazol-4-yl)methyl carbamate derivatives were designed and synthesized exploiting a copper- catalyzed [3+2] cycloaddition reaction between azides and alkynes (click chemistry). Exploration of the structure-activity relationships within this new class of compounds identified potent inhibitors of both rat and human FAAH with IC50 values in the single-digit nanomolar range. In addition, these derivatives showed improved stability in rat plasma and kinetic solubility in buffer with respect to the lead compound. Based on the results of the study, the novel analogues identified can be considered to be promising starting point for the development of new FAAH inhibitors with improved drug-like properties.
authors.affiliation: Drug Discovery & Development, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova (Italy); The Institute of Cancer Research, 15 Cotswold Rd, Sutton, Surrey SM2 5NG (UK). giampiero.colombano@iit.it, giampiero.colombano@icr.ac.uk.
authors.forename: Giampiero
authors.initials: G
authors.lastname: Colombano
authors.forename: Clara
authors.initials: C
authors.lastname: Albani
authors.forename: Giuliana
authors.initials: G
authors.lastname: Ottonello
authors.forename: Alison
authors.initials: A
authors.lastname: Ribeiro
authors.forename: Rita
authors.initials: R
authors.lastname: Scarpelli
authors.forename: Glauco
authors.initials: G
authors.lastname: Tarozzo
authors.forename: Jennifer
authors.initials: J
authors.lastname: Daglian
authors.forename: Kwang-Mook
authors.initials: KM
authors.lastname: Jung
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.forename: Tiziano
authors.initials: T
authors.lastname: Bandiera
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D002384:Catalysis; D057930:Click Chemistry; D003300:Copper / Q000737:chemistry; D061565:Cycloaddition Reaction; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D002219:Carbamates; D003300:Copper; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D000099252:Fatty Acid Amide Hydrolases; C036868:methyl carbamate
keywords: O-(triazolyl)methyl carbamates; click chemistry; fatty acid amide hydrolase (FAAH); inhibitors; structure-activity relationships