Exploration of orally available calpain inhibitors. Part 3: Dipeptidyl α-ketoamide derivatives containing pyridine moiety Original Research Article

Calpain-mediated proteolysis has been implicated as a major process in neuronal cell death including retinal neurological degeneration. The previously reported calpain inhibitor SJA6017 (1) showed oral efficacy in a retinal pharmacological model, but its oral bioavailability was low due to the metabolic lability and low water-solubility. The purpose of present study was to identify good orally bioavailable calpain inhibitors. A series of water-soluble dipeptidyl α-ketoamides containing a pyridine moiety at P3 were designed, synthesized, and evaluated for their oral bioavailability and retinal penetration. Introduction of a pyridineethanol moiety provided the potent α-ketoamide inhibitor 8 with good oral bioavailability. Compound 8 showed about 12-fold higher retinal AUC than 1.