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

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...

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Published inJournal 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
LanguageEnglish
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
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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 cis-hexahydro-pyrido-oxazinone (cis-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 cis-(4R,8S) HHPO headgroup was established, providing access to the highly potent and selective MAGL inhibitor 7o. Candidate molecule 7o 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.
AbstractList 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 cis-hexahydro-pyrido-oxazinone (cis-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 cis-(4R,8S) HHPO headgroup was established, providing access to the highly potent and selective MAGL inhibitor 7o. Candidate molecule 7o 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.
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 cis-hexahydro-pyrido-oxazinone (cis-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 cis-(4R,8S) HHPO headgroup was established, providing access to the highly potent and selective MAGL inhibitor 7o. Candidate molecule 7o 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.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 cis-hexahydro-pyrido-oxazinone (cis-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 cis-(4R,8S) HHPO headgroup was established, providing access to the highly potent and selective MAGL inhibitor 7o. Candidate molecule 7o 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.
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.
Author Koller, Raffael
Ruf, Iris
Richter, Hans
Hug, Melanie
van der Stelt, Mario
Gertsch, Jürg
Bürkler, Markus
Kocer, Buelent
Gobbi, Luca
Rombach, Didier
Kuratli, Martin
Topp, Andreas
Stihle, Martine
Benz, Jörg
Bartelmus, Christian
Wetzl, Dennis
Ritter, Martin
Pavlovic, Anto
O’Hara, Fionn
Grether, Uwe
Roth, Doris
Glasmacher, Sandra
Huber, Sylwia
Collin, Ludovic
Wittwer, Matthias Beat
Tosatti, Paolo
Guerard, Melanie
Schneider, Manfred
Heer, Dominik
Lutz, Marius D. R.
Saal, Wiebke
Bell, Charles
Stephanus, Juliane
Hornsperger, Benoit
Martella, Andrea
Kuhn, Bernd
Kroll, Carsten
AuthorAffiliation Roche Pharma Research and Early Development
NCCR TransCure, University of Bern
Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd
Department of Molecular Physiology
Institute of Biochemistry and Molecular Medicine
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/39360636$$D View this record in MEDLINE/PubMed
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Keywords POTENT
CANNABINOID RECEPTOR
ANANDAMIDE
DEGRADATION
MECHANISMS
BLOCKADE
PROTEINS
DERIVATIVES
AGONIST
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Snippet Monoacylglycerol lipase (MAGL) is a key enzyme involved in the metabolism of the endogenous signaling ligand 2-arachidonoylglycerol, a neuroprotective...
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StartPage 18448
SubjectTerms 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
Title Structure-Guided Discovery of cis-Hexahydro-pyrido-oxazinones as Reversible, Drug-like Monoacylglycerol Lipase Inhibitors
URI http://dx.doi.org/10.1021/acs.jmedchem.4c01769
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https://www.ncbi.nlm.nih.gov/pubmed/39360636
https://www.proquest.com/docview/3112529615
Volume 67
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