Novel cell-penetrating α-keto-amide calpain inhibitors as potential treatment for muscular dystrophy

Dipeptide-derived α-keto-amide compounds with potent calpain inhibitory activity have been identified. These reversible covalent inhibitors have IC50 values down to 25 nM and exhibit greatly improved activity in muscle cells compared to the reference compound MDL28170. Several novel calpain inhibitors have shown positive effects on histological parameters in an animal model of Duchenne muscular dystrophy demonstrating their potential as a treatment option for this fatal disease.

Graphical abstractThe synthesis of novel α-keto-amide calpain inhibitors bearing a lipoyl residue is reported. They demonstrated an improved activity in muscle cells compared to MDL28170, referring to increased cell membrane permeability.Figure optionsDownload full-size imageDownload as PowerPoint slide