Piperazine and Piperidine Triazole Ureas as Ultrapotent and Highly Selective Inhibitors of Monoacylglycerol Lipase

Abstract

Monoacylglycerol lipase (MAGL) terminates the signaling function of the endocannabinoid, 2-arachidonoylglycerol (2-AG). During 2-AG hydrolysis, MAGL liberates arachidonic acid, feeding the principal substrate for the neuroinflammatory prostaglandins. In cancer cells, MAGL redirects lipid stores toward protumorigenic signaling lipids. Thus MAGL inhibitors may have great therapeutic potential. Although potent and increasingly selective MAGL inhibitors have been described, their number is still limited. Here, we have characterized piperazine and piperidine triazole ureas that combine the high potency attributable to the triazole leaving group together with the bulky aromatic benzodioxolyl moiety required for selectivity, culminating in compound JJKK-048 that potently (IC50 < 0.4 nM) inhibited human and rodent MAGL. JJKK-048 displayed low cross-reactivity with other endocannabinoid targets. Activity-based protein profiling of mouse brain and human melanoma cell proteomes suggested high specificity also among the metabolic serine hydrolases.

Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain

“…When studying the mechanism of action of irreversible MGL inhibitors, we applied the concept advanced by Aaltonen and coworkers 16 according to whom the effects of the leaving group are strictly dependent upon its physicochemical properties, although steric hindrance may also play a role. In fact, we found that the effect on potency seems to be related to the pK a of the leaving group's conjugated acid (ideal pK a ∼ 10).…”

“…Crude title compound was used in the following step without any further purification (1.02 g, 81% yield). 1 3,4-Dihydro-2H-benzo [4,5]thiazolo[3,2-a]pyrimidine (16). To a stirred solution of alcohol 15 (1.02 g, 4.90 mmol) in dry dichloromethane (50.0 mL) cooled to 0°C, TEA (2.05 mL, 14.70 mmol) and mesyl chloride (570 μL, 7.35 mmol) were added and the mixture was stirred at 25°C under Ar atmosphere for 1.5 h. Methanol (300 μL) was added to quench the excess of mesyl chloride, and the reaction was treated with a further amount of TEA (2.05 mL, 14.70 mmol) and stirred at 50°C for 1.5 h. Water was added, and the aqueous phase was extracted with dichloromethane (3 × 15.0 mL).…”

“…9 Inhibitors of 2-AG degradation have been developed such as the carbamate biphenyl-3-ylcarbamic acid cyclohexyl ester (URB602), 10−12 the tetrahydrolipstatin (S)-1-((2S,3S)-3-hexyl-4-oxooxetan-2-yl)tridecan-2-yl 2-formamidoacetate (OMDM169), 13 the 4-(bis-benzo [1,3]dioxol-5-ylhydroxy-methyl)piperidine-1-carboxylic acid 4-nitro-phenyl ester 1 (JZL184), 14 the ureidic 4-(bis(4-fluorophenyl)methyl)-piperazin-1-yl)(1H-1,2,4-triazol-1-yl)methanone 2 (SAR629), 15 and their analogue (4-(bis(benzo[d] [1,3]dioxol-5-yl)methyl)-piperidin-1-yl)(1H-1,2,4-triazol-1-yl)methanone 3 (JJKK-048). 16 Despite the variety of MGL inhibitors available, the structural diversity of chemical templates explored to date remains poor. Compound 1, which shares with most MGL inhibitors the diphenylmethane core, is frequently used as experimental tool but it exhibits only submicromolar activity against the human MGL (hMGL) enzyme.…”

Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

“…153 Furthermore, compounds 146 (JJKK-046) and 147 (JJKK-048) ( Figure 54) were determined to inhibit hMAGL in the subnanomolar range (IC50 = 0.562 and 0.363 nM, respectively) and exert appreciable selectivity over several serine hydrolases, as shown using ABPP assays, including FAAH (SI > 1200 and 11200 fold, respectively), ABHD6 (SI > 150 and 600 fold, respectively). In addition, these two compounds exhibited no detectable potency against ABHD12 at a 1 μM concentration.…”

“…152 Recently, a series of piperazine/piperidine triazole ureas were described as highly selective MAGL inhibitors. 153 Structureactivity relationships illustrated that the Y-type scaffold of triazole ureas favors selectivity over FAAH.…”