Structure–activity relationship of human glutaminyl cyclase inhibitors having an N-(5-methyl-1H-imidazol-1-yl)propyl thiourea template
2013
Trà̂n, Phương Thảo | Hoàng, Văn Hải | Thorat, Shivaji A. | Kim, Sung Eun | Ann, Jihyae | Chang, Yu Jin | Nam, Dong Woo | Song, Hyundong | Mook-Jung, Inhee | Lee, Jiyoun | Lee, Jeewoo
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 58nM, 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-Aβ and Aβ plaques in cells and transgenic animals.
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