Title: Discovery of a Brain-Sparing GIRK1/4 Ion Channel Inhibitor for Pharmacological Cardioversion of Atrial Fibrillation.
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 the risk to induce lethal ventricular arrhythmia. Atrial-selective ion channel drugs are expected to restore and maintain sinus rhythm without the risk of ventricular arrhythmia. One such atrial-selective channel target is GIRK1/4 (G-protein regulated inwardly rectifying potassium channel 1/4). However, preceding GIRK1/4 clinical compounds were dose-limited in clinical trials, possibly due to central adverse effects caused by inhibition of the closely related GIRK1/2 channels present in the CNS. We describe the hit finding approaches and our medicinal chemistry strategy to minimize brain exposure to reduce central toxicity as an alternative to ion channel isoform selectivity. We describe multiple approaches to reduce brain exposure and the use of an acute rat toxicity model to evaluate central toxicity in vivo, resulting in a clinical candidate. Phase 1 clinical data shows the translatability of our preclinical toxicity assessment into healthy volunteers, ultimately demonstrating target engagement.
Bio: Dr. Peukert studied chemistry as an undergraduate at the University of Freiburg (Germany), Cambridge University (UK) and Stanford University (USA). He obtained his PhD in organic chemistry from the University of Basel (Switzerland) in 1998 under the guidance of Prof. Bernd Giese working on mechanistic studies and synthetic applications of the radical-induced heterolytic bond cleavage. After postdoctoral research with Prof. Eric Jacobson at Harvard University on synthetic applications of solid-phase supported Co(salen) complexes he started his career in the pharmaceutical industry at Aventis (now Sanofi) in Frankfurt. For five years he worked as a medicinal chemist on cardiovascular programs. In 2004 he joined Global Discovery Chemistry at the Novartis Institutes of Biomedical Research (Cambridge, USA), where he is currently leading a group in cardiovascular and metabolism chemistry and has additional responsibilities for external drug discovery and innovation. During this tenure with Novartis he has been involved in programs for infectious disease, oncology, cardiovascular and diabetes resulting in multiple compounds reaching clinical trials including the FDA/EMA approved Smoothened inhibitor Odomzo. In recent years he worked with the Novartis business development group to generate growth opportunities for the company portfolio of innovative medicines. His scientific work has been documented in numerous invited lectures and more than 60 book chapters, publications, and patent applications.