Ryanodine‐1‐Calstabin Complex Stabilizers in Antidoping Research: Synthesis, Metabolism, and Characterization

Awareness of new potential doping agents and the proactive implementation of detection methods are key aspects of preventive antidoping research. Ryanodine receptor-1-calstabin complex stabilizers (RYR-stabilizers) are a novel class of drug candidates for the treatment of various diseases associated with leaky Ca²⁺ channels in the cardiac or skeletal muscle. Also, intense physical activity was shown to transiently cause leakage of skeletal muscle Ca²⁺ channels, and RYR-stabilizers have been shown to restore normal activity and, thus, increase endurance performance. Consequently, such compounds are relevant targets in doping controls, and to date, in particular, compounds S107, JTV-519, ARM 036, and ARM 210 have been subject of antidoping research. In this study, ARM 036 and ARM 210 as well as the commercially available compounds S107 and JTV-519 were synthesized using a multistep approach. Subsequently, all compounds were investigated concerning their in vitro metabolic behavior, and various metabolites were identified. Selected metabolites were then chemically synthesized for comprehensive structure confirmation. The findings of this study will contribute to routine doping control analytical programs and allow for improving existing detection methods.