title: Structure-activity relationship of human glutaminyl cyclase inhibitors having an N-(5-methyl-1H-imidazol-1-yl)propyl thiourea template.
abstract: 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-Aβ and Aβ plaques in cells and transgenic animals.
authors: Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors: Phuong-Thao
authors: PT
authors: Tran
authors: Van-Hai
authors: VH
authors: Hoang
authors: Shivaji A
authors: SA
authors: Thorat
authors: Sung Eun
authors: SE
authors: Kim
authors: Jihyae
authors: J
authors: Ann
authors: Yu Jin
authors: YJ
authors: Chang
authors: Dong Woo
authors: DW
authors: Nam
authors: Hyundong
authors: H
authors: Song
authors: Inhee
authors: I
authors: Mook-Jung
authors: Jiyoun
authors: J
authors: Lee
authors: Jeewoo
authors: J
authors: Lee
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase; D013890:Thiourea