Aaltonen_2013_Chem.Biol_20_379

Reference

Title : Piperazine and piperidine triazole ureas as ultrapotent and highly selective inhibitors of monoacylglycerol lipase - Aaltonen_2013_Chem.Biol_20_379
Author(s) : Aaltonen N , Savinainen JR , Ribas CR , Ronkko J , Kuusisto A , Korhonen J , Navia-Paldanius D , Hayrinen J , Takabe P , Kasnanen H , Pantsar T , Laitinen T , Lehtonen M , Pasonen-Seppanen S , Poso A , Nevalainen T , Laitinen JT
Ref : Chemical Biology , 20 :379 , 2013
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.

PubMedSearch : Aaltonen_2013_Chem.Biol_20_379
PubMedID: 23521796
Gene_locus related to this paper: human-MGLL

Related information

Inhibitor AKU-005    JJKK-048
Gene_locus human-MGLL

Citations formats

Aaltonen N, Savinainen JR, Ribas CR, Ronkko J, Kuusisto A, Korhonen J, Navia-Paldanius D, Hayrinen J, Takabe P, Kasnanen H, Pantsar T, Laitinen T, Lehtonen M, Pasonen-Seppanen S, Poso A, Nevalainen T, Laitinen JT (2013)
Piperazine and piperidine triazole ureas as ultrapotent and highly selective inhibitors of monoacylglycerol lipase
Chemical Biology 20 :379

Aaltonen N, Savinainen JR, Ribas CR, Ronkko J, Kuusisto A, Korhonen J, Navia-Paldanius D, Hayrinen J, Takabe P, Kasnanen H, Pantsar T, Laitinen T, Lehtonen M, Pasonen-Seppanen S, Poso A, Nevalainen T, Laitinen JT (2013)
Chemical Biology 20 :379