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

[Display omitted] 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 ventricu...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 85; p. 129237
Main Authors:	Peukert, Stefan, Gulgeze Efthymiou, Hatice Belgin, Mo, Ruowei, Peng, Yunshan, Ma, Fupeng, Barbe, Guillaume, Bebernitz, Gregory, Fridrich, Cary, Buono, Chiara, Williams, Eric T., Daniels, Thomas, Li, Lisha, Zhang, Xia, Adachi, Yuichiro, Abe, Mie, Taggart, Andrew K.P.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-04-2023
Subjects:	Atrial fibrillation Atrial Fibrillation - drug therapy Brain Cardioversion Electric Countershock GIRK1/4 inhibitor Heart Atria Humans Peripherally restricted drug Cardioversion GIRK1/4 inhibitor Atrial fibrillation Peripherally restricted drug
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Summary:	[Display omitted] 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2023.129237