Synthesis, structure, and activity of diclofenac analogues as transthyretin amyloid fibril formation inhibitors. |
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Authors: | 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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Institution: | Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, BCC 265, La Jolla, California 92037, USA. |
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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. |
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