title: Synthesis, structure, and activity of diclofenac analogues as transthyretin amyloid fibril formation inhibitors.
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.
authors.affiliation: 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.
authors.forename: Vibha B
authors.initials: VB
authors.lastname: Oza
authors.forename: Craig
authors.initials: C
authors.lastname: Smith
authors.forename: Prakash
authors.initials: P
authors.lastname: Raman
authors.forename: Edward K
authors.initials: EK
authors.lastname: Koepf
authors.forename: Hilal A
authors.initials: HA
authors.lastname: Lashuel
authors.forename: H Mike
authors.initials: HM
authors.lastname: Petrassi
authors.forename: Kyle P
authors.initials: KP
authors.lastname: Chiang
authors.forename: Evan T
authors.initials: ET
authors.lastname: Powers
authors.forename: James
authors.initials: J
authors.lastname: Sachettinni
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D011228:Prealbumin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000682:Amyloid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011228:Prealbumin; D004008:Diclofenac