Fiche publication
Date publication
juillet 2024
Journal
Journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DARCQ Emmanuel
Tous les auteurs :
Fer M, Amalric C, Arban R, Baron L, Ben Hamida S, Breh-Schlanser P, Cui Y, Darcq E, Eickmeier C, Faye V, Franchet C, Frauli M, Halter C, Heyer M, Hoenke C, Hoerer S, Hucke OT, Joseph C, Kieffer BL, Lebrun L, Lotz N, Mayer S, Omrani A, Recolet M, Schaeffer L, Schann S, Schlecker A, Steinberg E, Viloria M, Würstle K, Young K, Zinser A, Montel F, Klepp J
Lien Pubmed
Résumé
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 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 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.
Référence
J Med Chem. 2024 07 1;:
