Lipophilic versus hydrogen-bonding effect in P₃ on potency and selectivity of valine aspartyl ketones as caspase 3 inhibitors

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• 作者：Christophe Mellon ; Reneé ; Aspiotis ; Cameron W. Black ; Christopher I. Bayly ; Erich L. Grimm ; André ; Giroux ; Yongxin Han ; Elise Isabel ; Daniel J. McKay ; Donald W. Nicholson et al.
• 关键词：Caspase 3 inhibitors ketones hydrogen bond
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2005
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：2005
• 卷：15
• 期：17
• 页码：3886-3890
• 文件大小：154 K

摘要

Caspase 3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact in the treatment of several degenerative diseases. The P₁ aspartic acid residue is a required element of recognition for this enzyme that was maintained constant along with the adjacent natural valine as the P₂ group. The thiobenzylmethylketone warhead on the aspartate was conveniently handled through solid-phase synthesis allowing modification in the P₃ region that eventually led to simpler derivatives with increased potency against caspase 3. The key to such an effect is the introduction of hydroxyl group alpha to the P₃ carbonyl.