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

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• 作者：Yan Wang ; Shaojuan Jia ; Ben Tseng ; John Drewe ; Sui Xiong Cai
• 关键词：Caspases ; Inhibitors
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2007
• 出版时间：15 November 2007
• 年：2007
• 卷：17
• 期：22
• 页码：6178-6182
• 全文大小：142 K

文摘

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.