Brain Permeable Tafamidis Amide Analogs for Stabilizing TTR and Reducing APP Cleavage,ACS Medicinal Chemistry Letters

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Brain Permeable Tafamidis Amide Analogs for Stabilizing TTR and Reducing APP Cleavage
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-03-12 , DOI: 10.1021/acsmedchemlett.9b00688
Anjana Sinha ₁ , Jerry C Chang _{1,

2} , Peng Xu ₁ , Katherina Gindinova ₁ , Younhee Cho ₃ , Weilin Sun ₁ , Xianzhong Wu ₂ , Yue Ming Li ₂ , Paul Greengard ₁ , Jeffery W Kelly ₃ , Subhash C Sinha ₁

Affiliation

Tafamidis, 1, a potent transthyretin kinetic stabilizer, weakly inhibits the γ-secretase enzyme in vitro. We have synthesized four amide derivatives of 1. These compounds reduce production of the Aβ peptide in N2a695 cells but do not inhibit the γ-secretase enzyme in cell-free assays. By performing fluorescence correlation spectroscopy, we have shown that TTR inhibits Aβ oligomerization and that addition of tafamidis or its amide derivative does not affect TTR’s ability to inhibit Aβ oligomerization. The piperazine amide derivative of tafamidis (1a) efficiently penetrates and accumulates in mouse brain and undergoes proteolysis under physiological conditions in mice to produce tafamidis.

中文翻译：

用于稳定 TTR 和减少 APP 裂解的脑渗透性 Tafamidis 酰胺类似物

Tafamidis, 1是一种有效的转甲状腺素蛋白动力学稳定剂，在体外微弱地抑制 γ-分泌酶。我们合成了1的四种酰胺衍生物。这些化合物可减少 N2a695 细胞中 Aβ 肽的产生，但在无细胞测定中不会抑制 γ-分泌酶。通过荧光相关光谱分析，我们发现TTR抑制Aβ寡聚化，并且添加tafamidis或其酰胺衍生物不会影响TTR抑制Aβ寡聚化的能力。 tafamidis的哌嗪酰胺衍生物( 1a )在小鼠大脑中高效渗透和积聚，并在小鼠生理条件下进行蛋白水解，产生tafamidis。

更新日期：2020-03-12

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