Design of β-Secretase Inhibitors by Introduction of a Mandelyl Moiety in DAPT Analogues
Design of β-Secretase Inhibitors by Introduction of a Mandelyl Moiety in DAPT Analogues
复制标题
通过在 DAPT 类似物中引入扁桃基部分设计 β-分泌酶抑制剂
DOI：
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发表时间：
2005
期刊：
影响因子：
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通讯作者：
J. Kraus
中科院分区：
文献类型：
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作者：
N. Pietrancosta;G. Quéléver;Y. Laras;C. Garino;Stéphane Burlet;J. Kraus
我们报道了两个系列的化合物的合成与3，5-二氟扁桃基-丙氨酰或3，5-二氟苯乙酰基-丙氨酰骨干耦合到各种杂环或肽部分。评价了这两个系列化合物对β-分泌酶（BACE-1）酶促测定的抑制特性，β-分泌酶（BACE-1）是阿尔茨海默病（AD）病理的靶酶。我们发现，从带有扁桃基部分的香豆素衍生物的外消旋混合物7中获得的两种非对映异构体是本研究中研究的最有效的BACE-1抑制剂（IC 50 = 1 × 10−6 M）。对所得结果的分析导致以下假设：引入二氟扁桃基残基代替二氟苯乙酰基部分可诱导β-分泌酶抑制活性。
We report the synthesis of two series of compounds with 3,5-difluoromandelyl-alanyl or 3,5-difluorophenylacetyl-alanyl backbones coupled to various heterocyclic or peptidic moieties. These two series of compounds were evaluated for their inhibitory properties on β-secretase (BACE-1) enzymatic assay, a target enzyme for Alzheimer’s disease (AD) pathology. We found that both diastereomers obtained from the racemic mixture 7 of the coumarin derivative bearing a mandelyl moiety were the most potent BACE-1 inhibitors studied in this work (IC50 = 1 × 10−6 M). Analysis of the obtained results led to the hypothesis that introduction of a difluoromandelyl residue in place of a difluorophenylacetyl moiety may induce β-secretase inhibitory activity.