Synthesis and Characterization of the Novel Rodent-Active and CNS-Penetrant P2X7 Receptor Antagonist Lu AF27139


Journal of Medicinal Chemistry


Allen T. Hopper*, Martin Juhl, Jorrit Hornberg, Lassina Badolo, John Paul Kilburn, Annemette Thougaard, Gennady Smagin, Dekun Song, Londye Calice, Veena Menon, Elena Dale, Hong Zhang, Manuel Cajina, Megan E. Nattini, Adarsh Gandhi, Michel Grenon, Ken Jones, Tanzilya Khayrullina, Gamini Chandrasena, Christian Thomsen, Stevin H. Zorn, Robb Brodbeck, Suresh Babu Poda, Roland Staal, and Thomas Möller



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.

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