Dipeptidyl aspartyl fluoromethylketones as potent caspase inhibitors: Peptidomimetic replacement of the P2 amino acid by 2-aminoaryl acids and other non-natural amino acids

As a continuation of our SAR studies of dipeptidyl aspartyl-fmk as caspase inhibitors, we explored the replacement of the P2 amino acid by a 2-aminoaryl acid or other non-natural amino acids. Several of these compounds, such as 6l and 6p, were found to have good activities with inhibition potencies of around 100 nM in a caspase-3 enzyme assay. EP1113, Z-Val-(2-aminobenzoyl)-Asp-fmk (9b), is identified as a potent broad-spectrum caspase inhibitor with IC50 values of 6–60 nM in different caspases. EP1113 also has good activity in a cell apoptosis protection assay.

The synthesis and biological evaluation of a group of peptidomimetic 2-(Z-amino)benzamide-aspartyl fluoromethylketones and related compounds as caspase inhibitors are reported.Figure optionsDownload as PowerPoint slide