title: Identification and characterization of carprofen as a multitarget fatty acid amide hydrolase/cyclooxygenase inhibitor.
abstract: Pain and inflammation are major therapeutic areas for drug discovery. Current drugs for these pathologies have limited efficacy, however, and often cause a number of unwanted side effects. In the present study, we identify the nonsteroidal anti-inflammatory drug carprofen as a multitarget-directed ligand that simultaneously inhibits cyclooxygenase-1 (COX-1), COX-2, and fatty acid amide hydrolase (FAAH). Additionally, we synthesized and tested several derivatives of carprofen, sharing this multitarget activity. This may result in improved analgesic efficacy and reduced side effects (Naidu et al. J. Pharmacol. Exp. Ther.2009, 329, 48-56; Fowler, C. J.; et al. J. Enzyme Inhib. Med. Chem.2012, in press; Sasso et al. Pharmacol. Res.2012, 65, 553). The new compounds are among the most potent multitarget FAAH/COX inhibitors reported so far in the literature and thus may represent promising starting points for the discovery of new analgesic and anti-inflammatory drugs.
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy.
authors.forename: Angelo D
authors.initials: AD
authors.lastname: Favia
authors.forename: Damien
authors.initials: D
authors.lastname: Habrant
authors.forename: Rita
authors.initials: R
authors.lastname: Scarpelli
authors.forename: Marco
authors.initials: M
authors.lastname: Migliore
authors.forename: Clara
authors.initials: C
authors.lastname: Albani
authors.forename: Sine Mandrup
authors.initials: SM
authors.lastname: Bertozzi
authors.forename: Mauro
authors.initials: M
authors.lastname: Dionisi
authors.forename: Glauco
authors.initials: G
authors.lastname: Tarozzo
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.forename: Marco
authors.initials: M
authors.lastname: De Vivo
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry*; D001665:Binding Sites; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry*; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D007124:Immunoenzyme Techniques; D062105:Molecular Docking Simulation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002227:Carbazoles; D016861:Cyclooxygenase Inhibitors; D000099252:Fatty Acid Amide Hydrolases; C007005:carprofen