Discovery of a brain-sparing GIRK1/4 inhibitor for pharmacological cardioversion of atrial fibrillation

Bioorg Med Chem Lett. 2023 Mar 15;85:129237. doi: 10.1016/j.bmcl.2023.129237. Online ahead of print.ABSTRACTAtrial fibrillation (AF) is the most common cardiac arrhythmia, and a significant risk factor for ischemic stroke and heart failure. Marketed anti-arrhythmic drugs can restore sinus rhythm, but with limited efficacy and significant toxicities, including potential to induce ventricular arrhythmia. Atrial-selective ion channel drugs are expected to restore and maintain sinus rhythm without risk of ventricular arrhythmia. One such atrial-selective channel target is GIRK1/4 (G-protein regulated inwardly rectifying potassium channel 1/4). Here we describe 14b, a potent GIRK1/4 inhibitor developed to cardiovert AF to sinus rhythm while minimizing central nervous system exposure - an issue with preceding GIRK1/4 clinical candidates.PMID:36924945 | DOI:10.1016/j.bmcl.2023.129237

Source: Bioorganic and Medicinal Chemistry Letters - March 16, 2023 Category: Chemistry Authors: Stefan Peukert Hatice Belgin Gulgeze Efthymiou Ruowei Mo Yunshan Peng Fupeng Ma Guillaume Barbe Gregory Bebernitz Cary Fridrich Chiara Buono Eric T Williams Thomas Daniels Lisha Li Xia Zhang Yuichiro Adachi Mie Abe Andrew K P Taggart Source Type: research