Structure-activity relationship of human glutaminyl cyclase inhibitors having an N-(5-methyl-1H-imidazol-1-yl)propyl thiourea template

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• 作者：Phuong-Thao Tran^a ; Van-Hai Hoang^a ; Shivaji A. Thorat^a ; Sung Eun Kim^a ; Jihyae Ann^a ; Yu Jin Chang^b ; Dong Woo Nam^b ; Hyundong Song^b ; Inhee Mook-Jung^b ; Jiyoun Lee^c ; Jeewoo Lee^a ; ^{jeewoo@snu.ac.kr}
• 关键词：Glutaminyl cyclase ; QC ; Alzheimer&rsquo ; s disease ; Beta amyloid ; Pyroglutamate ; Enzyme inhibitor
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：1 July, 2013
• 年：2013
• 卷：21
• 期：13
• 页码：3821-3830
• 全文大小：3897 K

文摘

In an effort to design inhibitors of human glutaminyl cyclase (QC), we have synthesized a library of N-aryl N-(5-methyl-1H-imidazol-1-yl)propyl thioureas and investigated the contribution of the aryl region of these compounds to their structure-activity relationships as cyclase inhibitors. Our design was guided by the proposed binding mode of the preferred substrate for the cyclase. In this series, compound 52 was identified as the most potent QC inhibitor with an IC₅₀ value of 58 nM, which was two-fold more potent than the previously reported lead 2. Compound 52 is a most promising candidate for future evaluation to monitor its ability to reduce the formation of pGlu-A¦Â and A¦Â plaques in cells and transgenic animals.