Bernd Kuhn, Martin Ritter, Benoit Hornsperger, Charles Bell, Buelent Kocer, Didier Rombach, Marius D R Lutz, Luca Gobbi, Martin Kuratli, Christian Bartelmus, Markus Bürkler, Raffael Koller, Paolo Tosatti, Iris Ruf, Melanie Guerard, Anto Pavlovic, Juliane Stephanus, Fionn O'Hara, Dennis Wetzl, Wiebke Saal, Martine Stihle, Doris Roth, Melanie Hug, Sylwia Huber, Dominik Heer, Carsten Kroll, Andreas Topp, Manfred Schneider, Jürg Gertsch, Sandra Glasmacher, Mario van der Stelt, Andrea Martella, Matthias Beat Wittwer, Ludovic Collin, Jörg Benz, Hans Richter, Uwe Grether
{"title":"Structure-Guided Discovery of <i>cis</i>-Hexahydro-pyrido-oxazinones as Reversible, Drug-like Monoacylglycerol Lipase Inhibitors.","authors":"Bernd Kuhn, Martin Ritter, Benoit Hornsperger, Charles Bell, Buelent Kocer, Didier Rombach, Marius D R Lutz, Luca Gobbi, Martin Kuratli, Christian Bartelmus, Markus Bürkler, Raffael Koller, Paolo Tosatti, Iris Ruf, Melanie Guerard, Anto Pavlovic, Juliane Stephanus, Fionn O'Hara, Dennis Wetzl, Wiebke Saal, Martine Stihle, Doris Roth, Melanie Hug, Sylwia Huber, Dominik Heer, Carsten Kroll, Andreas Topp, Manfred Schneider, Jürg Gertsch, Sandra Glasmacher, Mario van der Stelt, Andrea Martella, Matthias Beat Wittwer, Ludovic Collin, Jörg Benz, Hans Richter, Uwe Grether","doi":"10.1021/acs.jmedchem.4c01769","DOIUrl":null,"url":null,"abstract":"<p><p>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 <i>cis</i>-hexahydro-pyrido-oxazinone (<i>cis</i>-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 <i>cis</i>-(4<i>R</i>,8<i>S</i>) HHPO headgroup was established, providing access to the highly potent and selective MAGL inhibitor <b>7o</b>. Candidate molecule <b>7o</b> 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.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"18448-18464"},"PeriodicalIF":6.8000,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.4c01769","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/3 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.