Synthesis, pharmacological evaluation, and structure-activity relationships studies of sulfur-containing organic derivatives as monoacylglycerol lipase inhibitors

The Monoacylglycerol lipase (MAGL), a lipase hydrolyzing the endocannabinoid 2-arachidonoylglycerol, is considered as a promising target for the treatment of disease states such pain, inflammation and cell proliferation. The aim of the present work is the design, synthesis and establishment of structure-activity relationships of selective and potent monoacylglycerol lipase inhibitors. In the beginning of our study, as the three-dimensional structure of MAGL was not yet elucidated, screening of our own chemical library was performed in order to identify new chemical entities capable of inhibiting MAGL. We have identified the arylthioamide template as privileged scaffold for designing novel monoacylglycerol lipase inhibitors, and have highlighted the role of thiocarbamoyl group in enzyme inhibition. The second part of this work focused on the structure-activity relationships studies performed around disulfiram, in order to increase its activity and selectivity for MAGL inhibition. Indeed, among the incentives to initiate such an endeavour, in addition to containing thiocarbamoyl moiety, like arythioamide derivatives, disulfiram MAGL inhibitory properties have been evidenced in our laboratory. The pharmacomodulations carried out led to the identification of potent and selective disulfide-based MAGL inhibitors. Within the bis(dialkylaminethiocarbonyl)disulfide derivatives series, bis(4-methyl-1-piperazinylthiocarbonyl)disulfide was the most potent and selective MAGL inhibitor. These derivatives irreversibly inhibit MAGL through interaction with Cys208 and Cys242. Finally, as our group reported the MAGL 3D structure (Labar et al., 2010) and we demonstrated that the arylthioamide derivatives, identified as MAGL inhibitors by the screening of our chemical library, could constitute a useful template for designing novel MAGL inhibitors, we have undertaken chemical modifications around this scaffold in order to increase the potency and selectivity for MAGL inhibition as well as to establish the SAR of these new inhibitors. Since potent MAGL inhibitors such as JZL184 as well as triazolopyridine or triazolopyrimidine carboxamides derivatives have been reported to interact optimally with the acyl-binding pocket through a sterically hindered lipophilic moiety, we have developed a series of compounds based on the benzhydrylpiperazine template. The influence of lipophilicity, electronic properties, and conformational behavior was studied; the most potent and selective monoacylglycerol lipase inhibition was observed with 2,4-dinitroaryldithiocarbamate derivatives. These compounds bearing an excellent 2,4-dinitrothiophenolate leaving group irreversibly inhibit MAGL through interaction with the Cys208 or Cys242 and the catalytic Ser122 of MAGL. Among synthesized compounds, [2,4-dinitrophenyl-4-benzhydrylpiperazine-1-carbodithioate] (CK16) and [2,4-dinitrophenyl-4-(4-tert-butylbenzyl) piperazine-1-carbodithioate] (CK37) are the most selective and the potent MAGL inhibitors within this series, respectively. Furthermore, CK37 raises 2-arachidonoylglycerol levels in intact cells. We have demonstrated the MAGL inhibitory properties of sulfur-containing organic derivatives. The efficacy in inhibiting pure MAGL in vitro, coupled to the ability, in case of CK37, to increase cellular levels of 2-AG in intact cells, makes this derivative a promising MAGL inhibitor, which should prove useful for future investigation of endocannabinoid degradation pathways.(FARM 3) -- UCL, 201