Brain permeable tafamidis amide analogs for stabilizing TTR and reducing APP cleavage Research Letter
| Authors: | Sinha, A.; Chang, J. C.; Xu, P.; Gindinova, K.; Cho, Y.; Sun, W.; Wu, X.; Li, Y. M.; Greengard, P.; Kelly, J. W.; Sinha, S. C. |
| Title: | Brain permeable tafamidis amide analogs for stabilizing TTR and reducing APP cleavage |
| 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. Copyright © 2020 American Chemical Society. |
| Keywords: | transthyretin; prodrug; alzheimer's disease; γ-secretase; aβ peptide; tafamidis |
| Journal Title: | ACS Medicinal Chemistry Letters |
| Volume: | 11 |
| Issue: | 10 |
| ISSN: | 1948-5875 |
| Publisher: | American Chemical Society |
| Date Published: | 2020-10-10 |
| Start Page: | 1973 |
| End Page: | 1979 |
| Language: | English |
| DOI: | 10.1021/acsmedchemlett.9b00688 |
| PROVIDER: | scopus |
| PMCID: | PMC7549266 |
| PUBMED: | 33062181 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2020 -- Source: Scopus |
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