Inhibitors for Human Glutaminyl Cyclase by Structure Based Design and Bioisosteric Replacement

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• 作者：Mirko Buchholz ; Antje Hamann ; Susanne Aust ; Wolfgang Brandt ; Livia Bhme ; Torsten Hoffmann ; Stephan Schilling ; Hans-Ulrich Demuth ; Ulrich Heiser
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：November 26, 2009
• 年：2009
• 卷：52
• 期：22
• 页码：7069-7080
• 全文大小：1032K
• 年卷期：v.52,no.22(November 26, 2009)
• ISSN：1520-4804

文摘

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 Aβ_{3,11(pE)-40,42}, as these Aβ-species were shown to be of elevated neurotoxicity and likely to act as a seeding core leading to an accelerated formation of Aβ-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 Aβ_{3,11(pE)-40,42} formation.