2. Academic Validation
  3. Piperazine and piperidine triazole ureas as ultrapotent and highly selective inhibitors of monoacylglycerol lipase

Piperazine and piperidine triazole ureas as ultrapotent and highly selective inhibitors of monoacylglycerol lipase

  • Chem Biol. 2013 Mar 21;20(3):379-90. doi: 10.1016/j.chembiol.2013.01.012.
Niina Aaltonen 1,  Juha R Savinainen,  Casandra Riera Ribas,  Jani Rönkkö,  Anne Kuusisto,  Jani Korhonen,  Dina Navia-Paldanius,  Jukka Häyrinen,  Piia Takabe,  Heikki Käsnänen,  Tatu Pantsar,  Tuomo Laitinen,  Marko Lehtonen,  Sanna Pasonen-Seppänen,  Antti Poso,  Tapio Nevalainen,  Jarmo T Laitinen
Affiliations

Affiliation

  • 1 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
PMID: 23521796 DOI: 10.1016/j.chembiol.2013.01.012
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.

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