bis-furan derivatives as transthyretin stabilizers (ttr) and amyloid inhibitors for the treatment of familial amyloid polyneuropathy (fap).

摘要

bis-furan derivatives as transthyretin stabilizers (ttr) and amyloid inhibitors for the treatment of familial amyloid polyneuropathy (fap). The design and synthesis of a new bis-furan scaffold adapted for high efficiency in inhibiting amyloid transthyretin formation is reported. In vitro results show that the compounds discovered are more efficient inhibitors of amyloid formation than tafamidis, a drug currently used in the treatment of familial amyloid polyneuropathy (FAP), despite lower molecular weight and lipophilicity. In addition, ex vivo experiments with the strongest inhibitor in the series conducted in human blood plasma from normal transporters and fap val30met-transthyretin reveal remarkable profiles of affinity and selectivity. The promises and challenges faced by the development of this compound are discussed in light of the growing evidence that implies the stability of transthyretin as a key factor not only in transthyretin amyloidoses and various associated comorbidities, but also in Alzheimer's disease.