Development of pharmacological compounds to prevent RyR2 mediated intracellular Ca 2+ leak and to stabilize SERCA mediated Ca 2+ uptake to inhibit arrhythmia trigger mechanisms

Novel libraries of pharmacological RyR2 and SERCA stabilizing compounds are designed and synthesized after prior patent evaluation, by modification of structural elements of the reference compounds (Figure 7), and by application of the concept of bioisosterism (Figure 8). By this concept, particular functional groups of a molecule are replaced by other functional groups, without affecting or by even improving the desired bioactivity and/or selectivity. Initial hits are subsequently chemically optimized and tested in an iterative process. Simultaneously, all newly designed compounds are assessed by their ADMET-profile in silico.