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. 2023 Apr 1:85:129237.
doi: 10.1016/j.bmcl.2023.129237. Epub 2023 Mar 15.

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

Stefan Peukert  1 , Hatice Belgin Gulgeze Efthymiou  2 , Ruowei Mo  2 , Yunshan Peng  2 , Fupeng Ma  2 , Guillaume Barbe  2 , Gregory Bebernitz  3 , Cary Fridrich  2 , Chiara Buono  2 , Eric T Williams  2 , Thomas Daniels  2 , Lisha Li  2 , Xia Zhang  2 , Yuichiro Adachi  2 , Mie Abe  3 , Andrew K P Taggart  2
Affiliations

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

Stefan Peukert et al. Bioorg Med Chem Lett. .

Abstract

Atrial 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.

Keywords: Atrial fibrillation; Cardioversion; GIRK1/4 inhibitor; Peripherally restricted drug.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors are or have been employees of the Novartis Institutes of Biomedical Research and several of them are shareholders of Novartis.

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