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Synthesis of α-Ketoamide-Based Stereoselective Calpain-1 Inhibitors as Neuroprotective Agents.
ChemMedChem ( IF 3.4 ) Pub Date : 2020-08-24 , DOI: 10.1002/cmdc.202000385
Ammar Jastaniah 1 , Irina N Gaisina 1 , Rachel C Knopp 1 , Gregory R J Thatcher 1
Affiliation  

Calpain inhibitors have been proposed as drug candidates for neurodegenerative disorders, with ABT‐957 entering clinical trials for Alzheimer's disease and mild cognitive impairment. The structure of ABT‐957 was very recently disclosed, and trials were terminated owing to inadequate CNS concentrations to obtain a pharmacodynamic effect. The multistep synthesis of an α‐ketoamide peptidomimetic inhibitor series potentially including ABT‐957 was optimized to yield diastereomerically pure compounds that are potent and selective for calpain‐1 over papain and cathepsins B and K. As the final oxidation step, with its optimized synthesis protocol, does not alter the configuration of the substrate, the synthesis of the diastereomeric pair (R)‐1‐benzyl‐N‐((S)‐4‐((4‐fluorobenzyl)amino)‐3,4‐dioxo‐1‐phenylbutan‐2‐yl)‐5‐oxopyrrolidine‐2‐carboxamide (1 c) and (R)‐1‐benzyl‐N‐((R)‐4‐((4‐fluorobenzyl)amino)‐3,4‐dioxo‐1‐phenylbutan‐2‐yl)‐5‐oxopyrrolidine‐2‐carboxamide (1 g) was feasible. This allowed the exploration of stereoselective inhibition of calpain‐1, with 1 c (IC50=78 nM) being significantly more potent than 1 g. Moreover, inhibitor 1 c restored cognitive function in amnestic mice.

中文翻译:

基于 α-酮酰胺的立体选择性 Calpain-1 抑制剂作为神经保护剂的合成。

钙蛋白酶抑制剂已被提议作为神经退行性疾病的候选药物,ABT-957 已进入阿尔茨海默病和轻度认知障碍的临床试验。ABT-957 的结构最近才被公开,由于 CNS 浓度不足以获得药效学效果,试验被终止。对可能包括 ABT-957 的 α-酮酰胺类肽模拟抑制剂系列的多步合成进行了优化,以产生非对映异构纯的化合物,这些化合物对 calpain-1 比木瓜蛋白酶和组织蛋白酶 B 和 K 更有效且具有选择性。作为最后的氧化步骤,其优化合成方案,不改变底物的构型,非对映体对 ( R )-1-苄基-N -(( S)-4 - ((4-氟苄基)氨基)-3,4-二氧代-1-苯基丁-2-基)-5-氧代吡咯烷-2-甲酰胺(图1c)和(- [R)-1-苄基- ñ - (( R )-4-((4-fluorobenzyl)amino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide ( 1 g ) 是可行的。这允许探索 calpain-1 的立体选择性抑制,1 c (IC 50 =78 nM) 比1 g显着更有效。此外,抑制剂1c恢复了健忘症小鼠的认知功能。
更新日期:2020-08-24
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