9F8C

Crystal structure of human monoacylglycerol lipase in complex with compound 7m

This is a non-PDB format compatible entry.

Summary for 9F8C

• Entry DOI: 10.2210/pdb9f8c/pdb
• Descriptor: Monoglyceride lipase, (4~{a}~{R},8~{a}~{R})-6-[4-[[4-(trifluoromethyl)phenyl]methyl]piperidin-1-yl]carbonyl-4,4~{a},5,7,8,8~{a}-hexahydropyrido[4,3-b][1,4]oxazin-3-one, SODIUM ION, ... (5 entities in total)
• Functional Keywords: alpha/beta hydrolase, hydrolase, serine esterase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 36061.07

Authors

Kuhn, B.,Ritter, M.,Hornsperger, B.,Bell, C.,Kocer, B.,Rombach, D.,Richter, H.,Grether, U.,Gobbi, L.,Kuratli, M.,Collin, L.,Benz, J. (deposition date: 2024-05-06, release date: 2025-01-22)

Primary citation

Kuhn, B.,Ritter, M.,Hornsperger, B.,Bell, C.,Kocer, B.,Rombach, D.,Lutz, M.D.R.,Gobbi, L.,Kuratli, M.,Bartelmus, C.,Burkler, M.,Koller, R.,Tosatti, P.,Ruf, I.,Guerard, M.,Pavlovic, A.,Stephanus, J.,O'Hara, F.,Wetzl, D.,Saal, W.,Stihle, M.,Roth, D.,Hug, M.,Huber, S.,Heer, D.,Kroll, C.,Topp, A.,Schneider, M.,Gertsch, J.,Glasmacher, S.,van der Stelt, M.,Martella, A.,Wittwer, M.B.,Collin, L.,Benz, J.,Richter, H.,Grether, U.
Structure-Guided Discovery of cis -Hexahydro-pyrido-oxazinones as Reversible, Drug-like Monoacylglycerol Lipase Inhibitors.
J.Med.Chem., 67:18448-18464, 2024

PubMed Abstract: 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, a focused screening approach on a Roche library subset provided a reversible benzoxazinone hit exhibiting high ligand efficiency. The subsequent design of the three-dimensional -hexahydro-pyrido-oxazinone (-HHPO) moiety as benzoxazinone replacement enabled the combination of high MAGL potency with favorable ADME properties. Through enzymatic resolution an efficient synthetic route of the privileged -(4,8) HHPO headgroup was established, providing access to the highly potent and selective MAGL inhibitor . Candidate molecule matches the target compound profile of CNS drugs as it achieves high CSF exposures after systemic administration in rodents. It engages with the target in the brain and modulates neuroinflammatory processes, thus holding great promise for the treatment of CNS disorders.

PubMed: 39360636
DOI: 10.1021/acs.jmedchem.4c01769

Experimental method

X-RAY DIFFRACTION (1.52 Å)