BAY-6096: A Potent, Selective, and Highly Water-Soluble Adrenergic α_2B Antagonist

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. α_2B adrenergic receptors have been hypothesized to be involved in this process. To assess α_2B-related pharmacology, we identified a novel α_2B antagonist by HTS. The HTS hit showed limited α_2A selectivity as well as low solubility and was optimized toward BAY-6096, a potent, selective, and highly water-soluble α_2B 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 α_2B agonist, demonstrating the role of α_2B receptors in vascular constriction in rats.