A novel bis-furan scaffold for transthyretin stabilization and amyloid inhibition

作者：Simoes Carlos J V^*; Almeida Zaida L; Costa Dora; Jesus Catarina S H; Cardoso Ana L; Almeida Maria R; Saraiva Maria J; Pinho e Melo Teresa M V D; Brito Rui M M^*

来源：European Journal of Medicinal Chemistry, 2016, 121: 823-840.

DOI：10.1016/j.ejmech.2016.02.074

• Neurodegeneration
• Amyloid
• Transthyretin
• Lead discovery
• Bis-furans

The design and synthesis of a novel bis-furan scaffold tailored for high efficiency at inhibiting transthyretin amyloid formation is reported. In vitro results show that the discovered compounds are more efficient inhibitors of amyloid formation than tafamidis, a drug currently used in the treatment of familial amyloid polyneuropathy (FAP), despite their lower molecular weight and lipophilicity. Moreover, ex vivo experiments with the strongest inhibitor in the series, conducted in human blood plasma from normal and FAP VaI30Met-transthyretin carriers, disclose remarkable affinity and selectivity profiles. The promises and challenges facing further development of this compound are discussed under the light of increasing evidence implicating transthyretin stability as a key factor not only in transthyretin amyloidoses and several associated co -morbidities, but also in Alzheimer's disease.

• 出版日期2016-10-4