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 evaluate potential inhibitors of transthyretin (TTR) amyloid fibril formation in vitro. Twenty nine aromatic small molecules, some with homology to flufenamic acid (a known non-steroidal anti-inflammatory drug) were tested to identify important structural features for inhibitor efficacy. The results of these experiments and earlier data suggest that likely inhibitors will have aromatic-based structures with at least two aromatic rings. The ring or fused ring system occupying the outermost TTR binding pocket needs to be substituted with an acidic functional group (e.g. a carboxylic acid) to interact with complimentary charges in the TTR binding site. The promising TTR amyloid fibril inhibitors ranked in order of efficacy are: 2 > 4 approximately 7 > 3 > 9 > 6 > 21.
Baures
P W
PW
Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Oza
V B
VB
Peterson
S A
SA
Kelly
J W
JW
D000682:Amyloid / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D004061:Diflunisal / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005439:Flufenamic Acid / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008027:Light; D009544:Niflumic Acid / Q000737:chemistry / Q000494:pharmacology; D011228:Prealbumin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012542:Scattering, Radiation; D013329:Structure-Activity Relationship; D013467:Sulindac / Q000737:chemistry / Q000494:pharmacology; D014046:Tolmetin / Q000737:chemistry / Q000494:pharmacology
D000682:Amyloid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011228:Prealbumin; D013467:Sulindac; D009544:Niflumic Acid; D005439:Flufenamic Acid; D004061:Diflunisal; D014046:Tolmetin