Design, Synthesis and Pharmacological Evaluation of New Monoglyceride Lipase Inhibitors

Nicolas Matuszak, Geoffray Labar, Didier Lambert. Université Catholique de Louvain, Bruxelles, Belgium.

The increasing complexity of the endocannabinoid system is underlined by the identification of a growing number of endocannabinoids as well as pathways responsible for their synthesis and degradation. Among these endogenous ligands, 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid in the brain, shows useful pharmacological properties in neuroprotection, appetite regulation, cell proliferation, activity on prostate cancer(2). However, its effects are limited by a rapid metabolism to arachidonic acid and glycerol.

Among the enzymes known to hydrolyse 2-AG, monoglyceride lipase (MGL) is thought to be of prime importance in the regulation of 2-AG signalling. (1) (3) Indeed, the prevalent role of MGL within the endocannabinoid system has been highlighted by the SiRNA technique. Therefore, the selective inhibition of MGL constitutes a promising therapeutic approach.

Along these lines a series of 2-oleoylglycerol derivatives and a family of maleimides were designed, synthesized and tested on a recombinant MGL and on the human Fatty Acid Amide Hydrolase (FAAH).

In the maleimide family, a first series of phenyl-maleimides was synthesized from maleic anhydride and the appropriate phenylamines. A second series was synthesized following the Mitsunobu procedure, using the maleimide and the appropriate alcohol.

Among the phenylmaleimide derivatives synthesized (1), many compounds presented moderated inhibition of MGL with pI50 values ranging from 5.06 to 5.91. The best inhibition was observed with halogen-substituted compounds (para-bromophenyl-maleimide and para-chlorophenyl-maleimide), with pI50 of 5.8 and 5.9 on recombinant MGL. Among the second series, the N-palmitoylmaleimide was the best inhibitor with a pI50 of 7.0 (2)

The N-palmitoylmaleimide (2) constitutes, so far, the best inhibitor of our series. Moreover, we observed that a non polar, bulky substituent is needed for the compounds to exhibit good inhibitory activity. Compounds with a fatty acid chain moiety gave the most interesting results and we can therefore hypothesize that this hydrophobic moiety fits a lipophilic cavity of MGL(4).

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