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

Authors :
Catarina S. H. Jesus
Zaida L. Almeida
Maria João Saraiva
Rui M. M. Brito
Ana L. Cardoso
Teresa M. V. D. Pinho e Melo
Maria Rosário Almeida
Carlos J. V. Simões
Dora C. S. Costa
Source :
European Journal of Medicinal Chemistry. 121:823-840
Publication Year :
2016
Publisher :
Elsevier BV, 2016.

Abstract

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 Val30Met-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.

Details

ISSN :
02235234
Volume :
121
Database :
OpenAIRE
Journal :
European Journal of Medicinal Chemistry
Accession number :
edsair.doi.dedup.....c38326efc34a64310cf7851dfac039d4
Full Text :
https://doi.org/10.1016/j.ejmech.2016.02.074