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

Steven Johnson, Stephen Connelly, Ian A. Wilson, Jeffery W. Kelly

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

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 Å) 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.

Original languageEnglish (US)
Pages (from-to)260-270
Number of pages11
JournalJournal of Medicinal Chemistry
Volume51
Issue number2
DOIs
StatePublished - Jan 24 2008
Externally publishedYes

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Prealbumin
Thyroid Hormones
Thyroid Hormone Receptors
Bearings (structural)
Cytoplasmic and Nuclear Receptors
Joining
Libraries
Screening
Blood
Substitution reactions
Crystal structure

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Biochemical and structural evaluation of highly selective 2-arylbenzoxazole-based transthyretin amyloidogenesis inhibitors. / Johnson, Steven; Connelly, Stephen; Wilson, Ian A.; Kelly, Jeffery W.

In: Journal of Medicinal Chemistry, Vol. 51, No. 2, 24.01.2008, p. 260-270.

Research output: Contribution to journalArticle

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