BAY-6096: A Potent, Selective, and Highly Water-Soluble Adrenergic α(2B) Antagonist

[Image: see text] 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.