Design and synthesis of calpain inhibitory 6-pyridone 2-carboxamide derivatives

Excessive calpain activation contributes to serious cellular damage in many pathological conditions. The involvement of μ-calpain in neurological disorders such as, stroke and Alzheimer's disease has attracted considerable interest in the use of calpain inhibitors as therapeutic agents. 6-Pyridone 2-carboxamides derived from ketoamides were synthesized as conformationally constrained structures resembling the well known peptidic μ-calpain inhibitor, MDL 28,170, and their μ-calpain inhibitory activities were evaluated. Of the compounds synthesized, compound 2a, which has a primary amide at warhead region of the inhibitor most potently inhibited μ-calpain with an IC50 value of 2.81 ± 1.26 μM, which is ca. 40-fold less than that of MDL 28,170.

6-Pyridone 2-carboxamides derived from ketoamides were synthesized as conformationally constrained structures of a well known peptidic μ-calpain inhibitor, MDL 28,170. Among synthesized, compound 2a, which has a primary amide at warhead region of enzymes showed the most potent μ-calpain inhibitory activity with an IC50 value of 2.81 μM.Figure optionsDownload as PowerPoint slide