Development of tau aggregation inhibitors for Alzheimer's disease.
A variety of human diseases are suspected to be directly linked to protein misfolding. Highly organized protein aggregates, called amyloid fibrils, and aggregation intermediates are observed; these are considered to be mediators of cellular toxicity and thus attract a great deal of attention from investigators. Neurodegenerative pathologies such as Alzheimer's disease account for a major part of these protein misfolding diseases. The last decade has witnessed a renaissance of interest in inhibitors of tau aggregation as potential disease-modifying drugs for Alzheimer's disease and other "tauopathies". The recent report of a phase II clinical trial with the tau aggregation inhibitor MTC could hold promise for the validation of the concept. This Review summarizes the available data concerning small-molecule inhibitors of tau aggregation from a medicinal chemistry point of view.
Bulic
Bruno
B
Max-Planck-Institute for Molecular Physiology, Dortmund, Germany. bruno.bulic@mpi-dortmund.mpg.de
Pickhardt
Marcus
M
Schmidt
Boris
B
Mandelkow
Eva-Maria
EM
Waldmann
Herbert
H
Mandelkow
Eckhard
E
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D000682:Amyloid / Q000037:antagonists & inhibitors; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors; D052160:Benzothiazoles; D016208:Databases, Factual; D006801:Humans; D024801:Tauopathies / Q000188:drug therapy; D013844:Thiazoles / Q000378:metabolism; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000682:Amyloid; D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D013844:Thiazoles; D016875:tau Proteins; C009462:thioflavin T