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  • br Introduction br Results br Discussion br Experimental


    Introduction Endocannabinoids, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) have been found in most mammalian tissues and they stimulate cannabinoid CB1 and CB2 receptor activity thereby modulating several physiological responses, including nociception, anxiety, and depression.1, 2 The two main enzymes involved in endocannabinoid degradation are monoacylglycerol lipase (MAGL) and fatty nefiracetam amide hydrolase (FAAH). Two additional endocannabinoid-hydrolyzing enzymes have recently been discovered: α/β-hydrolase domain containing serine hydrolases ABHD6 and ABHD12, which are described as complementary 2-AG-degrading enzymes in the brain. Inhibition of these enzymes leads to accumulation of endocannabinoids and inducement of cannabimimetic effects. FAAH is the primary AEA-degrading enzyme, but it is also capable of hydrolyzing other bioactive N-acylethanolamines (NAEs), such as N-palmitoylethanolamine (PEA),N-oleoylethanolamine (OEA) and the sleep-inducing lipid oleamide. Pharmacological inhibition of FAAH has been considered as potential therapeutic approach for the treatment of several nervous system disorders, including pain, inflammation, anxiety, and depression.2, 8, 9 MAGL inhibitors may have therapeutic potential in treatment of cancer and neuroinflammatory diseases. MAGL hydrolyzes 2-AG to arachidonic acid, from which cyclooxygenases can synthesize neuroinflammatory prostaglandins. Therefore, it is possible that inhibition of MAGL may be an alternative way to regulate prostaglandin production and to reduce inflammation in neurodegenerative diseases. In addition, MAGL has been shown to control lipid metabolism in cancer cells by promoting production of lipid molecules towards oncogenic lipid messengers. A large number of FAAH inhibitors have been described over the years, such as α-keto heterocycles, lactams, carbamates, and piperidine/piperazine based ureas. So far, the most promising irreversible FAAH inhibitors with respect to selectivity and potency are piperidine and piperazine urea compounds, such as PF-3845 and JNJ-1661010 (Fig. 1). The development of potent and selective MAGL inhibitors has been slower compared to that of FAAH due to only recent availability of X-ray crystal structural data.13, 14, 15 In the model by Sanofi-Aventis, the crystal structure of MAGL was built by complexing the enzyme with the piperazine triazole urea inhibitor SAR629. This structure was one starting point for our compound series of piperazine triazole urea compounds. Very recently, remarkable progress has been achieved in the discovery of potent and selective MAGL inhibitors. Cravatt and co-workers have reported MAGL selective piperidine carbamate based inhibitors JZL184 and KLM-29 and piperazine carbamate based dual FAAH–MAGL inhibitors, such as JZL195 (Fig. 1). Other very recently published piperidine/piperazine ureas are benzotriazol-1-yl carboxamides, such as ML30 (Fig. 1) by Lambert and co-workers and piperazine ureas (e.g., 60j) by Kono et al.17, 18 While writing this manuscript, Wilson and co-workers have reported radiosynthesis of carbamate- and urea-based MAGL inhibitors. In this work, we follow up our previous study, in which we have designed and characterized piperazine and piperidine triazole ureas as highly potent and MAGL-selective inhibitors culminating in the synthesis of JJKK-048, which appeared the most potent and MAGL selective inhibitor currently described (IC50<0.4nM). Here, we describe the further optimization of piperazine and piperidine carboxamides and carbamates as potent and selective MAGL/FAAH inhibitors or as dual FAAH/MAGL inhibitors.
    Chemistry (Benzhydrylpiperazin-1-yl)carboxamides 3a–f were synthesized by triphosgene-mediated coupling of benzhydrylpiperazine 1 with either with the appropriate aniline or heterocyclic amine (Scheme 1). Compounds 3g–h were synthesized as shown in Scheme 1 starting by carbamylation of the heterocyclic amines with phenyl (4a) or p-nitrophenyl chloroformate (4b) to give the phenyl carbonyl derivatives 5a–b. Subsequent urea formation of 5a–b with 1 yielded 3g–h.