Synthesis of α-Ketoamide-Based Stereoselective Calpain-1 Inhibitors as Neuroprotective Agents.
Synthesis of α-Ketoamide-Based Stereoselective Calpain-1 Inhibitors as Neuroprotective Agents.
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DOI：
10.1002/cmdc.202000385
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发表时间：
2020-12-03
期刊：
影响因子：
3.4
通讯作者：
Thatcher GRJ
中科院分区：
文献类型：
--
作者：
Jastaniah A;Gaisina IN;Knopp RC;Thatcher GRJ
钙蛋白酶抑制剂已被建议作为治疗神经退行性疾病的候选药物，ABT-957已进入治疗阿尔茨海默病和轻度认知障碍的临床试验。ABT-957的结构是最近披露的，由于中枢神经系统浓度不足而终止了试验，以获得药效学效果。对可能包括ABT957的α-酮酰胺类多肽抑制剂系列的多步合成进行了优化，以产生对木瓜蛋白酶和组织蛋白酶B和K有效和选择性的非对映异构体纯化合物。由于最终的氧化步骤及其优化的合成方案不改变底物的构型，合成非对映异构体对(R)-1-benzyl-N-((S)-4-((4-fluorobenzyl)amino)-3，4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide(1c)和(R)-1-benzyl-N-((R)-4-((4-fluorobenzyl)amino)-3，4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide(1g)是可行的。这使得对Calain-1的立体选择性抑制的探索成为可能，1c(IC50=78 nM)明显比1g更有效。此外，抑制剂1c还恢复了健忘症小鼠的认知功能。(R)-1-Benzyl-N-((S)-4-((4-fluorobenzyl)amino)-3，4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide(1c)是一种非常有效和选择性的Calain-1抑制剂，可在mAChR拮抗剂东莨菪碱阻断胆碱能信号导致健忘症的反应中恢复记忆。
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. Since 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 (1c) and (R)-1-benzyl-N-((R)-4-((4-fluorobenzyl)amino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide (1g) was feasible. This allowed for the exploration of stereoselective inhibition of calpain-1, with 1c (IC50 = 78 nM) being significantly more potent than 1g. Moreover, inhibitor 1c restored cognitive function in amnestic mice. (R)-1-Benzyl-N-((S)-4-((4-fluorobenzyl)amino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide (1c) is a very potent and selective calpain-1 inhibitor that restored memory in response to the blockade of cholinergic signaling by the mAChR antagonist scopolamine, leading to amnesia.
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