Discovery of BI-9508, a Brain-Penetrant GPR88-Receptor-Agonist Tool Compound for In Vivo Mouse Studies

  • J Med Chem. 2024 Jul 11;67(13):11296-11325. doi: 10.1021/acs.jmedchem.4c00665.
Mickael Fer  1 ,  Camille Amalric  1 ,  Roberto Arban  2 ,  Luc Baron  1 ,  Sami Ben Hamida  3  4 ,  Petra Breh-Schlanser  2 ,  Yunhai Cui  2 ,  Emmanuel Darcq  3  5 ,  Christian Eickmeier  2 ,  Vincent Faye  1 ,  Christel Franchet  1 ,  Mélanie Frauli  1 ,  Célia Halter  1 ,  Marjorie Heyer  1 ,  Christoph Hoenke  2 ,  Stefan Hoerer  2 ,  Oliver T Hucke  2 ,  Christophe Joseph  1 ,  Brigitte L Kieffer  3  5 ,  Louison Lebrun  1 ,  Noémie Lotz  1 ,  Stanislas Mayer  1 ,  Azar Omrani  2 ,  Mandy Recolet  1 ,  Laurent Schaeffer  1 ,  Stephan Schann  1 ,  Annette Schlecker  2 ,  Edith Steinberg  1 ,  Mélanie Viloria  1 ,  Klaus Würstle  2 ,  Kyle Young  2 ,  Alexander Zinser  2 ,  Florian Montel  2 ,  Julian Klepp  2
Affiliations
  • 1. Domain Therapeutics, 67400 Illkirch, France.
  • 2. Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach an der Riß, Germany.
  • 3. Douglas Research Center, Department of Psychiatry, McGill University, Montréal, Quebec H4H 1R3, Canada.
  • 4. INSERM UMR 1247- Research Group on Alcohol & Pharmacodependences (GRAP), Université de Picardie Jules Verne, 80000 Amiens, France.
  • 5. INSERM UMR-S1329, Strasbourg Translational Neuroscience & Psychiatry, University of Strasbourg, Strasbourg 67084, France.
PMID: 38949964 DOI: 10.1021/acs.jmedchem.4c00665
Abstract

Decreased activity and expression of the G-protein coupled receptor GPR88 is linked to many behavior-linked neurological disorders. Published preclinical GPR88 allosteric agonists all have in vivo pharmacokinetic properties that preclude their progression to the clinic, including high lipophilicity and poor brain penetration. Here, we describe our attempts to improve GPR88 agonists' drug-like properties and our analysis of the trade-offs required to successfully target GPR88's allosteric pocket. We discovered two new GPR88 agonists: One that reduced morphine-induced locomotor activity in a murine proof-of-concept study, and the atropoisomeric BI-9508, which is a brain penetrant and has improved pharmacokinetic properties and dosing that recommend it for future in vivo studies in rodents. BI-9508 still suffers from high lipophilicity, and research on this series was halted. Because of its utility as a tool compound, we now offer researchers access to BI-9508 and a negative control free of charge via Boehringer Ingelheim's open innovation portal opnMe.com.

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