Structure-Guided Discovery of cis-Hexahydro-pyrido-oxazinones as Reversible, Drug-like Monoacylglycerol Lipase Inhibitors

• Published in: Journal of medicinal chemistry Vol. 67; no. 20; pp. 18448 - 18464
• Main Authors: Kuhn, Bernd, Ritter, Martin, Hornsperger, Benoit, Bell, Charles, Kocer, Buelent, Rombach, Didier, Lutz, Marius D. R., Gobbi, Luca, Kuratli, Martin, Bartelmus, Christian, Bürkler, Markus, Koller, Raffael, Tosatti, Paolo, Ruf, Iris, Guerard, Melanie, Pavlovic, Anto, Stephanus, Juliane, O’Hara, Fionn, Wetzl, Dennis, Saal, Wiebke, Stihle, Martine, Roth, Doris, Hug, Melanie, Huber, Sylwia, Heer, Dominik, Kroll, Carsten, Topp, Andreas, Schneider, Manfred, Gertsch, Jürg, Glasmacher, Sandra, van der Stelt, Mario, Martella, Andrea, Wittwer, Matthias Beat, Collin, Ludovic, Benz, Jörg, Richter, Hans, Grether, Uwe
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.10.2024; Amer Chemical Soc
• Subjects: Animals; Chemistry, Medicinal; Drug Discovery; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Humans; Life Sciences & Biomedicine; Male; Mice; Molecular Structure; Monoacylglycerol Lipases - antagonists & inhibitors; Monoacylglycerol Lipases - metabolism; Oxazines - chemical synthesis; Oxazines - chemistry; Oxazines - pharmacokinetics; Oxazines - pharmacology; Pharmacology & Pharmacy; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacokinetics; Pyridines - pharmacology; Rats; Science & Technology; Structure-Activity Relationship; POTENT; CANNABINOID RECEPTOR; ANANDAMIDE; DEGRADATION; MECHANISMS; BLOCKADE; PROTEINS; DERIVATIVES; AGONIST

Monoacylglycerol lipase (MAGL) is a key enzyme involved in the metabolism of the endogenous signaling ligand 2-arachidonoylglycerol, a neuroprotective endocannabinoid intimately linked to central nervous system (CNS) disorders associated with neuroinflammation. In the quest for novel MAGL inhibitors...