title: 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.affiliation: Department of Medicinal Chemistry, ‡Department of Enzymology §Department of Preclinical Pharmacology, Probiodrug AG , Weinbergweg 22, 06120 Halle, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ramsbeck
authors.forename: Mirko
authors.initials: M
authors.lastname: Buchholz
authors.forename: Birgit
authors.initials: B
authors.lastname: Koch
authors.forename: Livia
authors.initials: L
authors.lastname: Böhme
authors.forename: Torsten
authors.initials: T
authors.lastname: Hoffmann
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
authors.forename: Ulrich
authors.initials: U
authors.lastname: Heiser
mesh_terms: D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase