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

Academic Article

Chiang, Kyle Ping, Ph.D. in Macromolecular and Cellular Structure and Chemistry, Scripps Research 2001 - 2006
Petrassi, Mike, Ph.D. in Chemistry, Scripps Research 1997 - 2001

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.

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