title: Development and characterization of endocannabinoid hydrolases FAAH and MAGL inhibitors bearing a benzotriazol-1-yl carboxamide scaffold.
abstract: A series of (1H-benzo[d][1,2,3]triazol-1-yl)(4-benzylpiperazin-1-yl)methanones and of (1H-benzo[d][1,2,3]triazol-1-yl)(4-phenylpiperazin-1-yl)methanones has been prepared and tested on human fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). In the benzylpiperazinyl series, compound 29 (ML30) exhibited an IC(50) value of 0.54 nM on MAGL, combined with a 1000-fold selectivity versus FAAH, while compounds 11 and 16 acted as potent dual FAAH-MAGL inhibitors (IC(50)<10 nM). In the phenylpiperazinyl series, compounds 37, 38, 42, and 43 displayed IC(50) values against MAGL in the nanomolar range, whilst being between one and two orders of magnitude less potent on the FAAH, while compounds 31 and 32 were potent FAAH inhibitors (IC(50)<20 nM) and over 12-fold selective versus MAGL. The key structural determinants driving the structure-activity relationships were explored by the minimization of the inhibitors inside the active site of both enzymes.
authors.affiliation: Sapienza Università di Roma, Dipartimento di Chimica e Tecnologie del Farmaco, P.le Aldo Moro 5, Rome 00185, Italy. ludovica.morera@yahoo.it
authors.forename: Ludovica
authors.initials: L
authors.lastname: Morera
authors.forename: Geoffray
authors.initials: G
authors.lastname: Labar
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ortar
authors.forename: Didier M
authors.initials: DM
authors.lastname: Lambert
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D008994:Monoacylglycerol Lipases; D010879:Piperazines; D014230:Triazoles; D000099252:Fatty Acid Amide Hydrolases; C579449:(1H-benzo(d)(1,2,3)triazol-1-yl)(4-benzylpiperazin-1-yl)methanone; C579450:(1H-benzo(d)(1,2,3)triazol-1-yl)(4-phenylpiperazin-1-yl)methanone