Bisaryloxime Ethers as Potent Inhibitors of Transthyretin Amyloid Fibril Formation

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.

Chemical and Biological Approaches for Adapting Proteostasis to Ameliorate Protein Misfolding and Aggregation Diseases-Progress and Prognosis

“…Cite this article as Cold Spring Harb Perspect Biol 2011;3:a004507 under physiological conditions, precluding amyloidogenesis (Miroy et al 1996;Baures et al 1998Baures et al , 1999Oza et al 1999Oza et al , 2002Klabunde et al 2000;Petrassi et al 2000Petrassi et al , 2005Green et al 2003;Hammarstrom et al 2003;Razavi et al 2003Razavi et al , 2005Adamski-Werner et al 2004;Miller et al 2004;Purkey et al 2004;Green et al 2005;Johnson et al 2005aJohnson et al ,b, 2008aJohnson et al ,b, 2009Wiseman et al 2005;Sekijima et al 2006;Tojo et al 2006;Choi et al 2010a,b;Connelly et al 2010). Tafamidis, a benzoxazole-based transthyretin kinetic stabilizer discovered in academia (Razavi et al 2003) and developed by FoldRx Pharmaceuticals, showing a 2 nM dissociation constant from transthyretin (Razavi et al 2003 Figure 14.…”

Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis

“…Typically, Ͻ1% of TTR in the plasma and cerebrospinal fluid is bound to thyroxine, allowing us to target these sites with other small aromatic molecules to prevent amyloidogenesis (36). By using both focused screening and structure-based design, our laboratory has previously reported several classes of compounds that are capable of inhibiting TTR fibril formation by binding to the thyroxine sites (37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47). Good inhibitors bind with high affinity, dissociate slowly, and exhibit high binding selectivity to TTR in the blood.…”

Novel Non-carboxylate Benzoylsulfonamide-Based Protein Tyrosine Phosphatase 1B Inhibitors with Non-competitive Actions

“…The starting material 1, which was prepared as described previously, 23) underwent condensation with sulfonamide 2A 24) to afford 3. Compound 3 was treated with HClO 4 in the presence of various aldehydes (4a, 4b, 4d, 4f, 4h, 4i, 4k, 4l, and 4n) [25][26][27][28] to give the corresponding oxime linker derivatives 5a, 5c, 5d, 5f, 5h, 5i, 5k, 5m, and 5o.…”