The first potent inhibitors for human glutaminyl cyclase: synthesis and structure-activity relationship.
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.
Buchholz
Mirko
M
Department of Medicinal Chemistry, Probiodrug AG, Weinbergweg 22, 06120 Halle, Germany.
Heiser
Ulrich
U
Schilling
Stephan
S
Niestroj
André J
AJ
Zunkel
Katrin
K
Demuth
Hans-Ulrich
HU
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
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