期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 17, 页码 6613-6625出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm4001709
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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 A beta(3(pE)-40,42) species which were shown to be of elevated neurotoidcity and are likely to act as a seeding core, leading to an accelerated formation of A beta-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 benzimidazoly1-1,3,4-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.
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