jm2c01690_si_004.pdb (372.18 kB)
BAY-6096: A Potent, Selective, and Highly Water-Soluble Adrenergic α2B Antagonist
datasetposted on 2023-03-18, 13:05 authored by Daniel Meibom, Jutta Meyer, Clemens-Jeremias von Buehler, Karl D. Collins, Stefanie Maassen, Kersten Matthias Gericke, Jörg Hüser, Joachim Mittendorf, Nuria Ortega Hernandez, Jens Schamberger, Jan Stampfuss, Alexander Straub, Afra Torge, Norbert Witowski, Frank Wunder
After acute myocardial infarction, early reperfusion is the most effective strategy for reducing cardiac damage and improving clinical outcome. However, restoring blood flow to the ischemic myocardium can paradoxically induce injury by itself (reperfusion injury), with microvascular dysfunction being one contributing factor. α2B adrenergic receptors have been hypothesized to be involved in this process. To assess α2B-related pharmacology, we identified a novel α2B antagonist by HTS. The HTS hit showed limited α2A selectivity as well as low solubility and was optimized toward BAY-6096, a potent, selective, and highly water-soluble α2B antagonist. Key aspects of the optimization were the introduction of a permanently charged pyridinium moiety to achieve very good aqueous solubility and the inversion of an amide to prevent genotoxicity. BAY-6096 dose-dependently reduced blood pressure increases in rats induced by an α2B agonist, demonstrating the role of α2B receptors in vascular constriction in rats.
restoring blood flowreducing cardiac damageparadoxically induce injuryone contributing factorimproving clinical outcomeacute myocardial infarctionreperfusion injury ),good aqueous solubility2b sub2a suboptimized toward baysoluble adrenergic αsoluble αlow solubilityearly reperfusionvascular constrictionprevent genotoxicitynovel αmicrovascular dysfunctionkey aspectsischemic myocardiumhighly watereffective strategyassess αadrenergic receptors