Synthesis and evaluation of inhibitors of transthyretin amyloid formation based on the non-steroidal anti-inflammatory drug, flufenamic acid

A light scattering-based amyloid fibril formation assay was employed to eva luate potential inhibitors of transthyretin (TTR) amyloid fibril formation in vitro. Twenty nine aromatic small molecules, some with homology to flufe namic acid (a known non-steroidal anti-inflammatory drug) were tested to id entify important structural features for inhibitor efficacy. The results of these experiments and earlier data suggest that likely inhibitors will hav e aromatic-based structures with at least two aromatic rings. The ring or f used ring system occupying the outermost TTR binding pocket needs to be sub stituted with an acidic functional group (e.g. a carboxylic acid) to intera ct with complimentary charges in the TTR binding site. The promising TTR am yloid fibril inhibitors ranked in order of efficacy are: 2 > 4 approximate to 7 > 3 > 9 > 6 > 21 (see Fig. 5). (C) 1999 Elsevier Science Ltd. All righ ts reserved.