Structure-activity relationships of benzimidazole-based glutaminyl cyclase inhibitors featuring a heteroaryl scaffold.

Abstract

Glutaminyl cyclase (hQC) has emerged as a new potential target for the treatment of Alzheimer's disease (AD). The inhibition of hQC prevents of the formation of the Aβ3(pE)-40,42 species which were shown to be of elevated neurotoxicity and are likely to act as a seeding core, leading to an accelerated formation of Aβ-oligomers and fibrils. This work presents a new class of inhibitors of hQC, resulting from a pharmacophore-based screen. Hit molecules were identified, containing benzimidazole as the metal binding group connected to 1,3,4-oxadiazole as the central scaffold. The subsequent optimization resulted in benzimidazolyl-1,3,4-thiadiazoles and -1,2,3-triazoles with an inhibitory potency in the nanomolar range. Further investigation into the potential binding mode of the new compound classes combined molecular docking and site directed mutagenesis studies.

• Authors: Daniel Ramsbeck, Mirko Buchholz, Birgit Koch, Livia Böhme, Torsten Hoffmann, Hans-Ulrich Demuth, Ulrich Heiser
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 17 Pg. 6613-25 (Sep 12 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 23886302 (Publication Type: Journal Article)

Chemical References

• Benzimidazoles
• Aminoacyltransferases
• glutaminyl-peptide cyclotransferase

Topics

• Aminoacyltransferases (antagonists & inhibitors, chemistry)
• Benzimidazoles (chemistry, pharmacology)
• Molecular Docking Simulation
• Spectrometry, Mass, Electrospray Ionization
• Structure-Activity Relationship