Ming Jiang, Mirjam C W Huizenga, Jonah L Wirt, Janos Paloczi, Avand Amedi, Richard J B H N van den Berg, Joerg Benz, Ludovic Collin, Hui Deng, Xinyu Di, Wouter F Driever, Bogdan I Florea, Uwe Grether, Antonius P A Janssen, Thomas Hankemeier, Laura H Heitman, Tsang-Wai Lam, Florian Mohr, Anto Pavlovic, Iris Ruf, Helma van den Hurk, Anna F Stevens, Daan van der Vliet, Tom van der Wel, Matthias B Wittwer, Constant A A van Boeckel, Pal Pacher, Andrea G Hohmann, Mario van der Stelt
Monoacylglycerol lipase (MAGL) regulates endocannabinoid 2-arachidonoylglycerol (2-AG) and eicosanoid signalling. MAGL inhibition provides therapeutic opportunities but clinical potential is limited by central nervous system (CNS)-mediated side effects. Here, we report the discovery of LEI-515, a peripherally restricted, reversible MAGL inhibitor, using high throughput screening and a medicinal chemistry programme. LEI-515 increased 2-AG levels in peripheral organs, but not mouse brain. LEI-515 attenuated liver necrosis, oxidative stress and inflammation in a CCl4 -induced acute liver injury model...
December 5, 2023: Nature Communications