title: 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.
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
authors.forename: Niina
authors.initials: N
authors.lastname: Aaltonen
authors.forename: Juha R
authors.initials: JR
authors.lastname: Savinainen
authors.forename: Casandra Riera
authors.initials: CR
authors.lastname: Ribas
authors.forename: Jani
authors.initials: J
authors.lastname: Rönkkö
authors.forename: Anne
authors.initials: A
authors.lastname: Kuusisto
authors.forename: Jani
authors.initials: J
authors.lastname: Korhonen
authors.forename: Dina
authors.initials: D
authors.lastname: Navia-Paldanius
authors.forename: Jukka
authors.initials: J
authors.lastname: Häyrinen
authors.forename: Piia
authors.initials: P
authors.lastname: Takabe
authors.forename: Heikki
authors.initials: H
authors.lastname: Käsnänen
authors.forename: Tatu
authors.initials: T
authors.lastname: Pantsar
authors.forename: Tuomo
authors.initials: T
authors.lastname: Laitinen
authors.forename: Marko
authors.initials: M
authors.lastname: Lehtonen
authors.forename: Sanna
authors.initials: S
authors.lastname: Pasonen-Seppänen
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.forename: Tapio
authors.initials: T
authors.lastname: Nevalainen
authors.forename: Jarmo T
authors.initials: JT
authors.lastname: Laitinen
mesh_terms: D000818:Animals; D052117:Benzodioxoles / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D000077489:Piperazine; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry*; D051381:Rats; D013379:Substrate Specificity; D014230:Triazoles / Q000737:chemistry*; D014508:Urea / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D052117:Benzodioxoles; D004791:Enzyme Inhibitors; C000619376:JJNK-048; D010879:Piperazines; D010880:Piperidines; D014230:Triazoles; D000077489:Piperazine; C032727:piperidine; D014508:Urea; D008994:Monoacylglycerol Lipases