| Abstract
| - Transthyretin (TTR) amyloidogenesis requires rate-limiting tetramer dissociation and partialmonomer denaturation to produce a misassembly competent species. This process has been followed byturbidity to identify transthyretin amyloidogenesis inhibitors including dibenzofuran-4,6-dicarboxylic acid(1). An X-ray cocrystal structure of TTR·12 reveals that it only utilizes the outer portion of the two thyroxinebinding pockets to bind to and inhibit TTR amyloidogenesis. Herein, structure-based design was employedto append aryl substituents at C1 of the dibenzofuran ring to complement the unused inner portion of thethyroxine binding pockets. Twenty-eight amyloidogenesis inhibitors of increased potency and dramaticallyincreased plasma TTR binding selectivity resulted. These function by imposing kinetic stabilization on thenative tetrameric structure of TTR, creating a barrier that is insurmountable under physiological conditions.Since kinetic stabilization of the TTR native state by interallelic trans suppression is known to amelioratedisease, there is reason to be optimistic that the dibenzofuran-based inhibitors will do the same. Preventingthe onset of amyloidogenesis is the most conservative strategy to intervene clinically, as it remains unclearwhich of the TTR misassembly intermediates results in toxicity. The exceptional binding selectivity enablesthese inhibitors to occupy the thyroxine binding site(s) in a complex biological fluid such as blood plasma,required for inhibition of amyloidogenesis in humans. It is now established that the dibenzofuran-basedamyloidogenesis inhibitors have high selectivity, affinity, and efficacy and are thus excellent candidates forfurther pharmacologic evaluation.
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