Please join Yale Chemistry for a Novartis Seminar in Organic Chemistry with Prof. Yang Yang, Assistant Professor, Department of Chemistry and Biochemistry, from University of California Santa Barbara, and Dr. Stefan Peukert from Novartis Institutes of Biomedical Research.
3:30 - 4:30 pm: Dr. Stefan Peukert- Seminar Title: “Discovery of a safe GIRK1/4 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 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 outline our 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 innovative acute rat toxicity model to evaluate central toxicity in vivo, resulting in our clinical candidate. We show data around the chemical stability of the lead compound and optimization of the formulation to provide a viable drug product for iv administration. Phase 1 clinical data shows the translatability of our preclinical toxicity assessment into healthy volunteers, ultimately demonstrating target engagement and enabling a Phase 2 study in a cohort of patients.
4:30 - 5:30 pm: Prof. Yang Yang- Seminar Title: “New Strategies for Stereoselective Radical Biocatalysis”
Abstract: Radical reactions have enjoyed widespread applications in both small molecule and macromolecule synthesis. However, it remains challenging to control the stereochemistry of radical transformations and to discover novel modes of radical catalysis which are not known in either organic chemistry or biochemistry. Combining synthetic chemistry, enzymology and protein engineering, our group advanced two new biocatalytic strategies for stereoselective free radical processes. First, by capitalizing on the innate redox properties of first-row transition-metal cofactors, we repurposed and evolved natural metalloproteins to catalyze unnatural radical reactions in a stereocontrolled fashion. Through a metalloenzyme-catalyzed halogen atom transfer mechanism (XAT, X = F, Cl, Br and I), a range of radical C–C, C–Br, and C–F bond forming reactions proceeded with excellent total turnover numbers (up to 20,000) and outstanding stereocontrol. Second, by merging visible light photoredox catalysis and biocatalysis, we advanced a novel mode of pyridoxal radical biocatalysis which is new to both chemistry and biology. Synergistic photobiocatalysis allowed us to repurpose structurally and functionally diverse pyridoxal phosphate (PLP)-dependent enzymes as radical enzymes, leading to novel radical PLP enzymology. Pyridoxal radical biocatalysis provides convergent, stereoselective, and protecting-group-free access to a range of useful non-canonical amino acids, including those bearing a stereochemical triad and/or tetrasubstituted stereocenters which remained difficult to prepare by other chemical and biocatalytic means. Furthermore, we demonstrate that the
For more information about Prof. Yang’s research: https://yang.chem.ucsb.edu/research
Faculty Host: Prof. Scott Miller
These seminars can be viewed online: Panopto