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

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

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

To develop potent and highly selective transthyretin (TTR) amyloidogenesis inhibitors, it is useful to systematically optimize the three substructural elements that compose a typical TTR kinetic stabilizer: the two aryl rings and the linker joining them. Herein, we evaluated 40 bisaryl molecules based on 10 unique linker substructures to determine how these linkages influence inhibitor potency and selectivity. These linkers connect one unsubstituted aromatic ring to either a 3,5-X2 or a 3,5-X2-4-OH phenyl substructure (X = Br or CH3). Coconsideration of amyloid inhibition and ex vivo plasma TTR binding selectivity data reveal that direct connection of the two aryls or linkage through nonpolar E-olefin or -CH2CH2- substructures generates the most potent and selective TTR amyloidogenesis inhibitors exhibiting minimal undesirable binding to the thyroid hormone nuclear receptor or the COX-1 enzyme. Five high-resolution TTR·inhibitor crystal structures (1.4-1.8 Å) provide insight into why such linkers afford inhibitors with greater potency and selectivity.

Original languageEnglish (US)
Pages (from-to)6348-6358
Number of pages11
JournalJournal of Medicinal Chemistry
Volume51
Issue number20
DOIs
StatePublished - Oct 23 2008
Externally publishedYes

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Prealbumin
Thyroid Hormone Receptors
Alkenes
Cytoplasmic and Nuclear Receptors
Amyloid
Enzymes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Toward optimization of the linker substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies. / Johnson, Steven; Connelly, Stephen; Wilson, Ian A.; Kelly, Jeffery W.

In: Journal of Medicinal Chemistry, Vol. 51, No. 20, 23.10.2008, p. 6348-6358.

Research output: Contribution to journalArticle

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