Structure鈥揂ctivity Relationships of Benzimidazole-Based Glutaminyl Cyclase Inhibitors Featuring a Heteroaryl Scaffold
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- 作者：Daniel Ramsbeck ; Mirko Buchholz ; Birgit Koch ; Livia B枚hme ; Torsten Hoffmann ; Hans-Ulrich Demuth ; Ulrich Heiser
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：September 12, 2013
- 年：2013
- 卷：56
- 期：17
- 页码：6613-6625
- 全文大小：507K
- 年卷期：v.56,no.17(September 12, 2013)
- ISSN：1520-4804
文摘
Glutaminyl cyclase (hQC) has emerged as a new potential target for the treatment of Alzheimer鈥檚 disease (AD). The inhibition of hQC prevents of the formation of the A尾3(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 A尾-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.