Johnson Steven M, 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
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
J Med Chem. 2005 Mar 10;48(5):1576-87. doi: 10.1021/jm049274d.
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.
血浆蛋白转甲状腺素蛋白（TTR）形成淀粉样纤维，这需要限速的四聚体解离和单体错误折叠，与多种人类疾病有关。淀粉样变可以通过天然状态稳定化来抑制，这是由小分子与TTR主要未被占据的甲状腺激素结合位点结合介导的。本文通过芳醛与芳氧基胺的简便缩合反应发现了新的天然状态稳定剂，得到了一个双芳醛肟醚文库。在该文库的95种化合物中，有31种是TTR淀粉样蛋白形成的体外活性抑制剂。在淀粉样变条件下，双芳醛肟醚选择性地稳定TTR的天然四聚体状态，而不是解离过渡态，导致解离活化能垒增加。几种双芳醛肟醚在人血浆中比其他众多血浆蛋白更能选择性地结合TTR，这是体内有效性的必要属性。虽然双芳醛肟醚容易通过N-O键断裂而降解，但它们与TTR的结合会减缓这一过程。此外，许多双芳醛肟醚的降解速率相对于血浆TTR的半衰期较慢。如果有必要，双芳醛肟醚文库为开发具有更优稳定性的结构类似抑制剂提供了有价值的构效关系见解。
