Structure-Guided Discovery of <i>cis</i>-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, 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.
Authors
- Benoit Hornsperger
- Manfred P Schneider
- Luca B. Gobbi (ORCID: https://orcid.org/0000-0002-0563-2491)
- Didier Rombach
- Hans Georg Richter (ORCID: https://orcid.org/0000-0002-7224-9388)
- Andrea Martella (ORCID: https://orcid.org/0000-0002-4680-7702)
- Jürg Gertsch (ORCID: https://orcid.org/0000-0003-0978-1555)
- Iris Ruf
- Sandra Glasmacher
- Matthias Wittwer (ORCID: https://orcid.org/0000-0003-1359-4795)
- Christian Bartelmus (ORCID: https://orcid.org/0000-0002-1527-4325)
- Sylwia Huber
- Markus Bürkler
- Paolo Tosatti
- Melanie Guérard
- M. Stihle
- Fionn O’Hara
- Doris Roth (ORCID: https://orcid.org/0000-0003-0411-3945)
- Raffael Koller (ORCID: https://orcid.org/0000-0002-1977-3199)
- Uwe Grether (ORCID: https://orcid.org/0000-0002-3164-9270)
- Anto Pavlovic (ORCID: https://orcid.org/0009-0002-9395-6740)
- Buelent Koçer
- Carsten Kroll (ORCID: https://orcid.org/0009-0005-8255-326X)
- Ludovic Collin (ORCID: https://orcid.org/0000-0002-6313-3244)
- Martin Ritter (ORCID: https://orcid.org/0000-0002-2657-3187)
- Bernd Kuhn (ORCID: https://orcid.org/0000-0002-4301-562X)
- Marius D. R. Lutz (ORCID: https://orcid.org/0000-0003-3842-2295)
- Charles Bell
- Mario van der Stelt (ORCID: https://orcid.org/0000-0002-1029-5717)
- Dominik Heer (ORCID: https://orcid.org/0009-0003-2089-4339)
- Andreas Topp (ORCID: https://orcid.org/0009-0002-5511-2870)
- Martin Kuratli
- Melanie N. Hug
- Wiebke Saal (ORCID: https://orcid.org/0000-0002-6777-8664)
- Dennis Wetzl (ORCID: https://orcid.org/0000-0003-3596-6633)
- Juliane Stephanus
- Jörg Benz
Institutions
- Roche (Switzerland) (CH)
- University of Bern (CH)
- Leiden University (NL)
- Oncode Institute (NL)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-10-03
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01769
- Citations
- 7
- Primary Topic
- Cannabis and Cannabinoid Research
- Type
- article
- Field-Weighted Citation Impact
- 3.13