Brain Permeable Tafamidis Amide Analogs for Stabilizing TTR and Reducing APP Cleavage. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • March 12, 2020

Identity

PubMed Central ID

  • PMC7549266

Scopus Document Identifier

  • 0032797389

Digital Object Identifier (DOI)

  • 10.1016/S1074-5521(99)80020-9

PubMed ID

  • 33062181

Additional Document Info

volume

  • 11

issue

  • 10