Bisaryloxime ethers as potent inhibitors of transthyretin amyloid fibril formation.
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.
Johnson
Steven M
SM
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Petrassi
H Michael
HM
Palaninathan
Satheesh K
SK
Mohamedmohaideen
Nilofar N
NN
Purkey
Hans E
HE
Nichols
Christopher
C
Chiang
Kyle P
KP
Walkup
Traci
T
Sacchettini
James C
JC
Sharpless
K Barry
KB
Kelly
Jeffery W
JW
D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004355:Drug Stability; D004987:Ethers / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D006834:Hydrazines / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry; D066298:In Vitro Techniques; D010091:Oximes / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry; D011228:Prealbumin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D013329:Structure-Activity Relationship; D014461:Ultracentrifugation
D000682:Amyloid; D004987:Ethers; D006834:Hydrazines; D010091:Oximes; D011228:Prealbumin