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

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.


Published in:
Journal of medicinal chemistry, 45, 2, 321-32
Year:
2002
Publisher:
American Chemical Society
ISSN:
0022-2623
Other identifiers:
Laboratories:




 Record created 2009-10-28, last modified 2018-03-17

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