Peukert, Stefan, Gulgeze Efthymiou, Hatice, Mo, Ruowei, Peng, Yunshan, Buono, Chiara, Daniels, Thomas, Zhang, Xia, Adachi, Yuichiro, Taggart, Andrew, Ma, Fupeng, Guillaume, Barbe, Gregory, Bebernitz, Cary, Fridrich, Eric, Williams, Lisha, Li and Mie, Abe (2023) Discovery of a brain sparing GIRK1/4 inhibitor for pharmacological cardioversion of atrial fibrillation. Bioorganic and medicinal chemistry letters, 85 (129237). pp. 1-6. ISSN 0960-894X

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.

Item Type:	Article
Keywords:	Medicinal chemistry, atrial fibrillation, lead optimzation
Date Deposited:	13 Jun 2023 00:45
Last Modified:	13 Jun 2023 00:45
URI:	https://oak.novartis.com/id/eprint/49338