Biochemical and structural evaluation of highly selective 2-arylbenzoxazole-based transthyretin amyloidogenesis inhibitors

J Med Chem. 2008 Jan 24;51(2):260-70. doi: 10.1021/jm0708735. Epub 2007 Dec 21.


To develop potent transthyretin (TTR) amyloidogenesis inhibitors that also display high binding selectivity in blood, it proves useful to systematically optimize each of the three substructural elements that comprise a typical inhibitor: the two aryl rings and the linker joining them. In the first study, described herein, structural modifications to one aryl ring were evaluated by screening a library of 2-arylbenzoxazoles bearing thyroid hormone-like aryl substituents on the 2-aryl ring. Several potent and highly selective amyloidogenesis inhibitors were identified that exhibit minimal thyroid hormone nuclear receptor and COX-1 binding. High resolution crystal structures (1.3-1.5 A) of three inhibitors (2f, 4f, and 4d) in complex with TTR were obtained to characterize their binding orientation. Collectively, the results demonstrate that thyroid hormone-like substitution patterns on one aryl ring lead to potent and highly selective TTR amyloidogenesis inhibitors that lack undesirable thyroid hormone receptor or COX-1 binding.

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*
  • Amyloid / blood
  • Amyloid / chemistry
  • Benzoxazoles / chemical synthesis*
  • Benzoxazoles / chemistry
  • Benzoxazoles / pharmacology
  • Crystallography, X-Ray
  • Cyclooxygenase 1 / chemistry
  • Cyclooxygenase Inhibitors / chemical synthesis
  • Cyclooxygenase Inhibitors / chemistry
  • Humans
  • In Vitro Techniques
  • Liver / metabolism
  • Models, Molecular
  • Prealbumin / antagonists & inhibitors*
  • Prealbumin / chemistry
  • Protein Conformation
  • Receptors, Thyroid Hormone / metabolism
  • Structure-Activity Relationship


  • Amyloid
  • Benzoxazoles
  • Cyclooxygenase Inhibitors
  • Prealbumin
  • Receptors, Thyroid Hormone
  • Cyclooxygenase 1

Associated data

  • PDB/2QGB
  • PDB/2QGC
  • PDB/2QGD
  • PDB/2QGE