Synthesis, structure, and activity of diclofenac analogues as transthyretin amyloid fibril formation inhibitors

Vibha B. Oza, Craig Smith, Prakash Raman, Edward K. Koepf, Hilal A. Lashuel, H. Mike Petrassi, Kyle P. Chiang, Evan T. Powers, James Sachettinni, Jeffery W. Kelly

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Abstract

Twelve analogues of diclofenac (1), a nonsteroidal antiinflammatory drug and known inhibitor of transthyretin (TTR) amyloid formation, were prepared and evaluated as TTR amyloid formation inhibitors. High activity was exhibited by five of the compounds. Structure-activity relationships reveal that a carboxylic acid is required for activity, but changes in its position as well as the positions of other substituents are tolerated. High-resolution X-ray crystal structures of four of the active compounds bound to TTR were obtained. These demonstrate the significant flexibility with which TTR can accommodate ligands within its two binding sites.

Original languageEnglish
Pages (from-to)321-332
Number of pages12
JournalJournal of Medicinal Chemistry
Volume45
Issue number2
DOIs
Publication statusPublished - 17 Jan 2002
Externally publishedYes

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ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Oza, V. B., Smith, C., Raman, P., Koepf, E. K., Lashuel, H. A., Petrassi, H. M., Chiang, K. P., Powers, E. T., Sachettinni, J., & Kelly, J. W. (2002). Synthesis, structure, and activity of diclofenac analogues as transthyretin amyloid fibril formation inhibitors. Journal of Medicinal Chemistry, 45(2), 321-332. https://doi.org/10.1021/jm010257n