Dipeptidyl aspartyl fluoromethylketones as potent caspase inhibitors: peptidomimetic replacement of the P 2 α-amino acid by a α-hydroxy acid

• Published in: Bioorganic & medicinal chemistry letters Vol. 15; no. 5; pp. 1379 - 1383
• Main Authors: Wang, Yan, Guan, Lufeng, Jia, Shaojuan, Tseng, Ben, Drewe, John, Cai, Sui Xiong
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.03.2005
• Subjects: Apoptosis; Caspase inhibitor; Caspase inhibitor; Apoptosis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.01.007

The synthesis and biological evaluation of a group of peptidomimetic α-carbamoyl-alkylcarbonyl-aspartyl fluoromethethylketones as capase inhibitors is reported. As a continuation of our SAR studies of dipeptidyl aspartyl-fmk as caspase inhibitors, we explored the replacement of the P 2 α-amino acid by a peptidomimetic α-hydroxy acid. These α-carbamoyl-alkylcarbonyl-aspartyl fluoromethylketones were found to be potent caspase inhibitors, and the SAR of these compounds is similar to the corresponding dipeptidyl aspartyl-fmk. MX1153, ( S)-3-methyl-2-(phenylcarbamoyl)butanoyl-Asp-fmk, is identified as a potent broad-spectrum caspase inhibitor, and is selective for caspases versus other proteases. MX1153 also has good activity in the cell apoptosis protection assays and is active in the mouse liver apoptosis model.