Translational Application of the Five-Star Matrix for the Structure-Guided Optimization of a Bicyclopiperazine DEL Hit into Bcpz 1.5: A Potent Monoacylglycerol Lipase Inhibitor with Functional Inhibition in Human Brain Homogenate and Efficacy in Neur
Abstract Monoacylglycerol lipase (MAGL) is a promising therapeutic target for neuroinflammatory conditions. We have previously reported on MAGLi 432, a reversible MAGL inhibitor with activity in mouse models of neuroinflammation. In this full account, we report on the structure-guided optimization of a bicyclopiperazine (Bcpz) DEL hit into potent, selective and brain-penetrant reversible MAGL inhibitor 1.5 (MAGLi 432), guided by the “Five-Star Matrix” translational framework. Compound 1.5 combines excellent MAGL potency (IC50 = 3.2 nM) and selectivity over other serine hydrolases with favorable pharmacokinetic properties, including a 5.7 h half-life after oral administration in male Wistar rats, and CNS drug-like potential. Furthermore, as previously reported, the compound demonstrated robust brain penetration and efficacy in preclinical mouse models of neuroinflammation correlating with inhibition of MAGL activity in mouse and human brain homogenate. This work highlights the power of combining DEL screening and SBDD with the Five-Star Matrix to deliver drug-like candidates for neuroinflammatory disorders.
Authors
- Axel Pähler
- Benoit Hornsperger
- Moreno Wichert (ORCID: https://orcid.org/0000-0001-9691-6934)
- Manfred P Schneider
- Luca B. Gobbi (ORCID: https://orcid.org/0000-0002-0563-2491)
- Hans Georg Richter (ORCID: https://orcid.org/0000-0002-7224-9388)
- Andrea Martella (ORCID: https://orcid.org/0000-0002-4680-7702)
- Iris Ruf
- Katrin Groebke Zbinden
- Matthias Wittwer (ORCID: https://orcid.org/0000-0003-1359-4795)
- Christian Bartelmus (ORCID: https://orcid.org/0000-0002-1527-4325)
- A. Haider (ORCID: https://orcid.org/0009-0005-3704-0908)
- Sylwia Huber
- Benjamin Brennecke
- Markus Bürkler
- Melanie Guérard
- Fionn O’Hara
- Martin Binder (ORCID: https://orcid.org/0009-0001-9686-7738)
- 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)
- Antonia F. Stepan (ORCID: https://orcid.org/0000-0003-2203-129X)
- Sina Simon (ORCID: https://orcid.org/0009-0008-2078-3635)
- Louise Plais (ORCID: https://orcid.org/0000-0002-0987-0585)
- Bernd Kuhn (ORCID: https://orcid.org/0000-0002-4301-562X)
- 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)
- Manuel Hilbert
- Maude Giroud (ORCID: https://orcid.org/0000-0001-6320-5546)
- Wiebke Saal (ORCID: https://orcid.org/0000-0002-6777-8664)
- Juliane Stephanus
- Remo Hochstrasser
- Jörg Benz
- Ann Petersen
- Satoshi Tsuchiya
- Martin Ritter
Institutions
- Roche (Switzerland) (CH)
- Leiden University (NL)
- ETH Zurich (CH)
- Roche (France) (FR)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-10-08
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c01872
- Primary Topic
- Computational Drug Discovery Methods
- Type
- article
- Field-Weighted Citation Impact
- 0.00