Bisaryloxime ethers as potent inhibitors of transthyretin amyloid fibril formation

Steven Johnson, H. Michael Petrassi, Satheesh K. Palaninathan, Nilofar N. Mohamedmohaideen, Hans E. Purkey, Christopher Nichols, Kyle P. Chiang, Traci Walkup, James C. Sacchettini, K. Barry Sharpless, Jeffery W. Kelly

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

Amyloid fibril formation by the plasma protein transthyretin (TTR), requiring rate-limiting tetramer dissociation and monomer misfolding, is implicated in several human diseases. Amyloidogenesis can be inhibited through native state stabilization, mediated by small molecule binding to TTR's primarily unoccupied thyroid hormone binding sites. New native state stabilizers have been discovered herein by the facile condensation of arylaldehydes with aryloxyamines affording a bisarylaldoxime ether library. Of the library's 95 compounds, 31 were active inhibitors of TTR amyloid formation in vitro. The bisaryloxime ethers selectively stabilize the native tetrameric state of TTR over the dissociative transition state under amyloidogenic conditions, leading to an increase in the dissociation activation barrier. Several bisaryloxime ethers bind selectively to TTR in human blood plasma over the plethora of other plasma proteins, a necessary attribute for efficacy in vivo. While bisarylaldoxime ethers are susceptible to degradation by N-O bond cleavage, this process is slowed by their binding to TTR. Furthermore, the degradation rate of many of the bisarylaldoxime ethers is slow relative to the half-life of plasma TTR. The bisaryloxime ether library provides valuable structure-activity relationship insight for the development of structurally analogous inhibitors with superior stability profiles, should that prove necessary.

Original languageEnglish (US)
Pages (from-to)1576-1587
Number of pages12
JournalJournal of Medicinal Chemistry
Volume48
Issue number5
DOIs
StatePublished - Mar 10 2005
Externally publishedYes

Fingerprint

Prealbumin
Ethers
Amyloid
Ether
Blood Proteins
Plasmas
Degradation
Structure-Activity Relationship
Thyroid Hormones
Libraries
Half-Life
Condensation
Blood
Stabilization
Monomers
Chemical activation
Binding Sites
Molecules

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Johnson, S., Petrassi, H. M., Palaninathan, S. K., Mohamedmohaideen, N. N., Purkey, H. E., Nichols, C., ... Kelly, J. W. (2005). Bisaryloxime ethers as potent inhibitors of transthyretin amyloid fibril formation. Journal of Medicinal Chemistry, 48(5), 1576-1587. https://doi.org/10.1021/jm049274d

Bisaryloxime ethers as potent inhibitors of transthyretin amyloid fibril formation. / Johnson, Steven; Petrassi, H. Michael; Palaninathan, Satheesh K.; Mohamedmohaideen, Nilofar N.; Purkey, Hans E.; Nichols, Christopher; Chiang, Kyle P.; Walkup, Traci; Sacchettini, James C.; Sharpless, K. Barry; Kelly, Jeffery W.

In: Journal of Medicinal Chemistry, Vol. 48, No. 5, 10.03.2005, p. 1576-1587.

Research output: Contribution to journalArticle

Johnson, S, Petrassi, HM, Palaninathan, SK, Mohamedmohaideen, NN, Purkey, HE, Nichols, C, Chiang, KP, Walkup, T, Sacchettini, JC, Sharpless, KB & Kelly, JW 2005, 'Bisaryloxime ethers as potent inhibitors of transthyretin amyloid fibril formation', Journal of Medicinal Chemistry, vol. 48, no. 5, pp. 1576-1587. https://doi.org/10.1021/jm049274d
Johnson S, Petrassi HM, Palaninathan SK, Mohamedmohaideen NN, Purkey HE, Nichols C et al. Bisaryloxime ethers as potent inhibitors of transthyretin amyloid fibril formation. Journal of Medicinal Chemistry. 2005 Mar 10;48(5):1576-1587. https://doi.org/10.1021/jm049274d
Johnson, Steven ; Petrassi, H. Michael ; Palaninathan, Satheesh K. ; Mohamedmohaideen, Nilofar N. ; Purkey, Hans E. ; Nichols, Christopher ; Chiang, Kyle P. ; Walkup, Traci ; Sacchettini, James C. ; Sharpless, K. Barry ; Kelly, Jeffery W. / Bisaryloxime ethers as potent inhibitors of transthyretin amyloid fibril formation. In: Journal of Medicinal Chemistry. 2005 ; Vol. 48, No. 5. pp. 1576-1587.
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