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Inhibitors for human glutaminyl cyclase by structure based design and bioisosteric replacement.

Authors
  • Buchholz, Mirko
  • Hamann, Antje
  • Aust, Susanne
  • Brandt, Wolfgang
  • Böhme, Livia
  • Hoffmann, Torsten
  • Schilling, Stephan
  • Demuth, Hans-Ulrich
  • Heiser, Ulrich
Type
Published Article
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society
Publication Date
Nov 26, 2009
Volume
52
Issue
22
Pages
7069–7080
Identifiers
DOI: 10.1021/jm900969p
PMID: 19863057
Source
Medline
License
Unknown

Abstract

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.

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