Toward optimization of the second aryl substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies

J Med Chem. 2009 Feb 26;52(4):1115-25. doi: 10.1021/jm801347s.


Transthyretin (TTR) amyloidogenesis inhibitors are typically composed of two aromatic rings and a linker. We have previously established optimal structures for one aromatic ring and the linker. Herein, we employ a suboptimal linker and an optimal aryl-X substructure to rank order the desirability of aryl-Z substructures--using a library of 56 N-(3,5-dibromo-4-hydroxyphenyl)benzamides. Coconsideration of amyloid inhibition potency and ex vivo plasma TTR binding selectivity data reveal that 2,6, 2,5, 2, 3,4,5, and 3,5 substituted aryls bearing small substituents generate the most potent and selective inhibitors, in descending order. These benzamides generally lack undesirable thyroid hormone receptor binding and COX-1 inhibition activity. Three high-resolution TTR.inhibitor crystal structures (1.31-1.35 A) provide insight into why these inhibitors are potent and selective, enabling future structure-based design of TTR kinetic stabilizers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amyloid / antagonists & inhibitors*
  • Amyloidosis / prevention & control*
  • Benzamides / chemistry*
  • Benzamides / pharmacology
  • Crystallography, X-Ray
  • Cyclooxygenase 1 / drug effects
  • Drug Design
  • Humans
  • Molecular Structure
  • Prealbumin / antagonists & inhibitors*
  • Receptors, Thyroid Hormone / metabolism
  • Structure-Activity Relationship


  • Amyloid
  • Benzamides
  • Prealbumin
  • Receptors, Thyroid Hormone
  • Cyclooxygenase 1

Associated data

  • PDB/3ESN
  • PDB/3ESO
  • PDB/3ESP