Brain Permeable Tafamidis Amide Analogs for Stabilizing TTR and Reducing APP Cleavage

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.