Event

The Novartis Lectureship in Chemical Sciences at the University of Pennsylvania
 
Stefan Peukert
Novartis Institutes for Biomedical Research
 
Discovery of a safe GIRK1/4 inhibitor for pharmacological cardioversion of atrial fibrillation
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 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 our clinical candidate HSY244. We show data around the chemical stability of the lead compound, an optimized scalable synthesis and identification of a viable formulation for iv administration. Phase 1 clinical data shows the translatability of our preclinical toxicity assessment into healthy volunteers, ultimately demonstrating target engagement. 
 
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.

 
Angela M. Gronenborn
University of Pittsburgh
 

The awesome power of fluorine NMR - from drugs to cells
Nuclear magnetic resonance (NMR) spectroscopy is a versatile tool for probing structure, dynamics, folding, and interactions at atomic resolution. While naturally occurring magnetically active isotopes, such as 1H, 13C, or 15N, are most commonly used in biomolecular NMR, with 15N and 13C isotopic labeling routinely employed at the present time, 19F is a very attractive and sensitive alternative nucleus, which offers rich information on biomolecules in solution and in the solid state. This presentation will summarize the unique benefits of solution, solid-state and in-cell 19F NMR spectroscopy for the study of biomolecular systems. Particular focus will be placed on the most recent studies and on unique and important potential applications of fluorine NMR methodology.

Angela M. Gronenborn currently holds the UPMC Rosalind Franklin Professorship and Chair of the Department of Structural Biology. She is also a Professor of Bioengineering and Chemistry at the University of Pittsburgh. She obtained her Ph.D. in organic chemistry from the University of Cologne (Germany). After post-doctoral training, she started her independent career at the National Institute of Medical Research in Mill Hill, London, and subsequently lead research groups at the Max Planck Institute in Munich, the Laboratory of Chemical Physics at the NIH and since 2006 at the University of Pittsburgh Medical School. Throughout her career, Dr. Gronenborn was involved in developing NMR methodology for characterizing structure, dynamics and function of biological macromolecules. In the area of HIV research, Dr. Gronenborn directs the Pittsburgh Center for HIV Protein Interactions (PCHPI).

Dr. Gronenborn serves on numerous Scientific Advisory Boards and held leadership positions in professional societies. She trained more than 50 graduate students and post-doctoral fellows and authored more that 500 peer-reviewed publications. She was elected to the National Academy of Sciences (US), the Norwegian Academy of Arts and Letters, the German National Academy of Sciences and the American Academy of Arts & Sciences.