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2 results on '"Viloria, Mélanie"'

1. Discovery of BI-9508, a Brain-Penetrant GPR88-Receptor-Agonist Tool Compound for In VivoMouse Studies

Author

Fer, Mickael, Amalric, Camille, Arban, Roberto, Baron, Luc, Ben Hamida, Sami, Breh-Schlanser, Petra, Cui, Yunhai, Darcq, Emmanuel, Eickmeier, Christian, Faye, Vincent, Franchet, Christel, Frauli, Mélanie, Halter, Célia, Heyer, Marjorie, Hoenke, Christoph, Hoerer, Stefan, Hucke, Oliver T., Joseph, Christophe, Kieffer, Brigitte L., Lebrun, Louison, Lotz, Noémie, Mayer, Stanislas, Omrani, Azar, Recolet, Mandy, Schaeffer, Laurent, Schann, Stephan, Schlecker, Annette, Steinberg, Edith, Viloria, Mélanie, Würstle, Klaus, Young, Kyle, Zinser, Alexander, Montel, Florian, and Klepp, Julian

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 vivopharmacokinetic 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 vivostudies 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.

Published
2024
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2. Discovery of BI-9508, a Brain-Penetrant GPR88-Receptor-Agonist Tool Compound for In Vivo Mouse Studies.

Author

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, and Klepp J

Subjects
Animals, Mice, Humans, Drug Discovery, Male, Structure-Activity Relationship, Mice, Inbred C57BL, Morphine pharmacology, Morphine pharmacokinetics, Receptors, G-Protein-Coupled agonists, Receptors, G-Protein-Coupled metabolism, Brain metabolism, Brain drug effects
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.

Published
2024
Full Text
View/download PDF

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