Tau protein and tau aggregation inhibitors.
Alzheimer disease is characterized by pathological aggregation of two proteins, tau and Abeta-amyloid, both of which are considered to be toxic to neurons. In this review we summarize recent advances on small molecule inhibitors of protein aggregation with emphasis on tau, with activities mediated by the direct interference of self-assembly. The inhibitors can be clustered in several compound classes according to their chemical structure, with subsequent description of the structure-activity relationships, showing that hydrophobic interactions are prevailing. The description is extended to the pharmacological profile of the compounds in order to evaluate their drug-likeness, with special attention to toxicity and bioavailability. The collected data indicate that following the improvements of the in vitro inhibitory potencies, the consideration of the in vivo pharmacokinetics is an absolute prerequisite for the development of compounds suitable for a transfer from bench to bedside.
Bulic
Bruno
B
Center for Advanced European Studies and Research, Bonn, Germany. bruno.bulic@caesar.de
Pickhardt
Marcus
M
Mandelkow
Eva-Maria
EM
Mandelkow
Eckhard
E
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D005419:Flavonoids / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions / Q000187:drug effects; D010636:Phenols / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D059808:Polyphenols; D012236:Rhodanine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016875:tau Proteins / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; D053778:Thiazolidines; D016875:tau Proteins; C038131:epalrestat; D012236:Rhodanine; D000449:Aldehyde Reductase