title: The first potent inhibitors for human glutaminyl cyclase: synthesis and structure-activity relationship.
abstract: The first effective inhibitors for human glutaminyl cyclase (QC) are described. The structures are developed by applying a ligand-based optimization approach starting from imidazole. Screening of derivatives of that heterocycle led to compounds of the imidazol-1-yl-alkyl thiourea type as a lead scaffold. A library of thiourea derivatives was synthesized, resulting in an inhibitory improvement by 2 orders of magnitude, leading to 1-(3-(1H-imidazol-1-yl)propyl)-3-(3,4-dimethoxyphenyl)thiourea as a potent inhibitor. Systematic exploitation of the scaffold revealed a strong impact on the inhibitory efficacy and resulted in the development of imidazole-propyl-thioamides as another new class of potent inhibitors. A flexible alignment of the most potent compounds of the thioamide and thiourea class and a QC substrate revealed a good match of characteristic features of the molecules, which suggests a similar binding mode of both inhibitors and the substrate to the active site of QC.
authors.affiliation: Department of Medicinal Chemistry, Probiodrug AG, Weinbergweg 22, 06120 Halle, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Buchholz
authors.forename: Ulrich
authors.initials: U
authors.lastname: Heiser
authors.forename: Stephan
authors.initials: S
authors.lastname: Schilling
authors.forename: André J
authors.initials: AJ
authors.lastname: Niestroj
authors.forename: Katrin
authors.initials: K
authors.lastname: Zunkel
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
mesh_terms: D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013854:Thioamides / Q000138:chemical synthesis* / Q000737:chemistry; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D015032:Zinc / Q000737:chemistry
chemical_list: C508799:1-(3-(1H-imidazol-1-yl)propyl)-3-(3,4,5-trimethoxyphenyl)thiourea; D002614:Chelating Agents; D007093:Imidazoles; C508800:N-(3-(1H-imidazol-1-yl)propyl)-1-(3,4-dimethoxyphenyl)cyclopropanecarbothioamide; D013854:Thioamides; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase; D013890:Thiourea; D015032:Zinc