Synthesis and Characterization of the Novel Rodent-Active and CNS-Penetrant P2X7 Receptor Antagonist Lu AF27139
| Autor: | Suresh Poda, Robb Brodbeck, Veena Menon, Manuel Cajina, Elena Dale, Annemette V. Thougaard, Martin Juhl, Londye Calice, Hopper Allen T, Thomas Möller, Roland G. W. Staal, Michel Grenon, Stevin H. Zorn, Kenneth A. Jones, Gamini Chandrasena, Tanzilya Khayrullina, Jorrit J. Hornberg, Lassina Badolo, John Paul Kilburn, Dekun Song, Adarsh Gandhi, Megan Nattini, Hong Zhang, Christian Thomsen, Gennady N. Smagin |
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| Rok vydání: | 2021 |
| Předmět: |
Central Nervous System
Lipopolysaccharides Male Microdialysis Purinergic P2X Receptor Antagonists Lipopolysaccharide Interleukin-1beta Pharmacology 01 natural sciences Monocytes Cell Line Rats Sprague-Dawley Mice 03 medical and health sciences chemistry.chemical_compound Adenosine Triphosphate Dogs Pharmacokinetics In vivo Drug Discovery Animals Humans Receptor 030304 developmental biology 0303 health sciences Antagonist Molecular Pharmacology In vitro Rats 0104 chemical sciences Mice Inbred C57BL 010404 medicinal & biomolecular chemistry chemistry Microsomes Liver Molecular Medicine Female Microglia Receptors Purinergic P2X7 Half-Life |
| Zdroj: | Journal of Medicinal Chemistry. 64:4891-4902 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.0c02249 |
| Popis: | There remains an insufficient number of P2X7 receptor antagonists with adequate rodent potency, CNS permeability, and pharmacokinetic properties from which to evaluate CNS disease hypotheses preclinically. Herein, we describe the molecular pharmacology, safety, pharmacokinetics, and functional CNS target engagement of Lu AF27139, a novel rodent-active and CNS-penetrant P2X7 receptor antagonist. Lu AF27139 is highly selective and potent against rat, mouse, and human forms of the receptors. The rat pharmacokinetic profile is favorable with high oral bioavailability, modest clearance (0.79 L/(h kg)), and good CNS permeability. In vivo mouse CNS microdialysis studies of lipopolysaccharide (LPS)-primed and 2'(3')-O-(benzoylbenzoyl)adenosine-5'-triphosphate (BzATP)-induced IL-1β release demonstrate functional CNS target engagement. Importantly, Lu AF27139 was without effect in standard in vitro and in vivo toxicity studies. Based on these properties, we believe Lu AF27139 will be a valuable tool for probing the role of the P2X7 receptor in rodent models of CNS diseases. |
| Databáze: | OpenAIRE |
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