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

Academic Article
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Overview

related to degree

  • 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

authors

  • Oza, V. B.
  • Smith, C.
  • Raman, P.
  • Koepf, E. K.
  • Lashuel, H. A.
  • Petrassi, Mike
  • Chiang, Kyle Ping
  • Powers, Evan
  • Sachettinni, J.
  • Kelly, Jeffery

publication date

  • January 2002

journal

  • Journal of Medicinal Chemistry  Journal

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.

subject areas

  • Amyloid
  • Anti-Inflammatory Agents, Non-Steroidal
  • Crystallography, X-Ray
  • Diclofenac
  • Models, Molecular
  • Molecular Structure
  • Prealbumin
  • Protein Binding
  • Structure-Activity Relationship
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Identity

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm010257n

PubMed ID

  • 11784137
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Additional Document Info

start page

  • 321

end page

  • 332

volume

  • 45

issue

  • 2

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