Inhibitors for human glutaminyl cyclase by structure based design and bioisosteric replacement.
The inhibition of human glutaminyl cyclase (hQC) has come into focus as a new potential approach for the treatment of Alzheimer's disease. The hallmark of this principle is the prevention of the formation of Abeta(3,11(pE)-40,42), as these Abeta-species were shown to be of elevated neurotoxicity and likely to act as a seeding core leading to an accelerated formation of Abeta-oligomers and fibrils. Starting from 1-(3-(1H-imidazol-1-yl)propyl)-3-(3,4-dimethoxyphenyl)thiourea, bioisosteric replacements led to the development of new classes of inhibitors. The optimization of the metal-binding group was achieved by homology modeling and afforded a first insight into the probable binding mode of the inhibitors in the hQC active site. The efficacy assessment of the hQC inhibitors was performed in cell culture, directly monitoring the inhibition of Abeta(3,11(pE)-40,42) formation.
Department of Medicinal Chemistry, Probiodrug AG, Weinbergweg 22, 06120 Halle, Germany.
Mirko
M
Buchholz
Antje
A
Hamann
Susanne
S
Aust
Wolfgang
W
Brandt
Livia
L
Böhme
Torsten
T
Hoffmann
Stephan
S
Schilling
Hans-Ulrich
HU
Demuth
Ulrich
U
Heiser
D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D002460:Cell Line; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000737:chemistry
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase; D013890:Thiourea; D011761:Pyrrolidonecarboxylic Acid