Synthesis and evaluation of calpain inhibitors carrying muscle cell targeting groups

Inhibition of the cysteine protease calpain is a promising strategy for the treatment of muscular dystrophies including Duchenne Muscular Dystrophy. For the treatment to be effective, uptake of the inhibitors into the muscle cells is a prerequisite. A series of alpha-ketoamide calpain inhibitors carrying various muscle cell targeting capping groups was synthesized. Compounds with charged or highly polar targeting groups were not able to cross the cellular membrane. Introduction of lipoic acid as end cap yielded cell permeable calpain inhibitors with nanomolar potency.