title: Synthesis and in vitro evaluation of N-substituted maleimide derivatives as selective monoglyceride lipase inhibitors.
abstract: The endocannabinoid 2-arachidonoylglycerol (2-AG) plays a major role in many physiological processes, and its action is quickly terminated via enzymatic hydrolysis catalyzed by monoglyceride lipase (MGL). Regulating its endogenous level could offer therapeutic opportunities; however, few selective MGL inhibitors have been described so far. Here, we describe the synthesis of N-substituted maleimides and their pharmacological evaluation on the recombinant human fatty acid amide hydrolase (FAAH) and on the purified human MGL. A few N-arylmaleimides were previously described ( Saario , S. M. ; Salo , O. M. ; Nevalainen , T. ; Poso , A. ; Laitinen , J. T. ; Jarvinen , T. ; Niemi , R. Characterization of the Sulfhydryl-Sensitive Site in the Enzyme Responsible for Hydrolysis of 2-Arachidonoylglycerol in Rat Cerebellar Membranes . Chem. Biol. 2005 , 12 , 649 - 656 ) as MGL inhibitors, and along these lines, we present a new set of maleimide derivatives that showed low micromolar IC(50) and high selectivity toward MGL vs FAAH. Then, structure-activity relationships have been investigated and, for instance, 1-biphenyl-4-ylmethylmaleimide inhibits MGL with an IC(50) value of 790 nM. Furthermore, rapid dilution experiments reveal that these compounds act as irreversible inhibitors. In conclusion, N-substituted maleimides constitute a promising class of potent and selective MGL inhibitors.
authors: Faculté de Medecine, Unité de Chimie Pharmaceutique et de Radiopharmacie, Louvain Drug Research Institute, Ecole de Pharmacie, Drug Design and Discovery Centre, Université Catholique de Louvain, B-1200 Bruxelles, Belgium.
authors: Nicolas
authors: N
authors: Matuszak
authors: Giulio G
authors: GG
authors: Muccioli
authors: Geoffray
authors: G
authors: Labar
authors: Didier M
authors: DM
authors: Lambert
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008301:Maleimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D008301:Maleimides; D008994:Monoacylglycerol Lipases; D000099252:Fatty Acid Amide Hydrolases; C043592:maleimide