Utilization of the 1,2,3,5-thiatriazolidin-3-one 1,1-dioxide scaffold in the design of potential inhibitors of human neutrophil proteinase 3

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 3; pp. 1093 - 1102
• Main Authors: Dou, Dengfeng, He, Guijia, Li, Yi, Lai, Zhong, Wei, Liuqing, Alliston, Kevin R., Lushington, Gerald H., Eichhorn, David M., Groutas, William C.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.02.2010; Elsevier
• Subjects: Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Crystallography, X-Ray; Humans; Inhibitors; Medical sciences; Models, Molecular; Myeloblastin - antagonists & inhibitors; Myeloblastin - chemistry; Myeloblastin - metabolism; Pharmacology. Drug treatments; Protein Binding; Proteinase 3; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacology; Triazoles - chemistry; Triazoles - pharmacology; Inhibitors; Proteinase 3; Human; Serine endopeptidases; Enzyme; In vitro; Modeling; Biological activity; Peptidases; Molecular model; Hydrolases; Inhibitor; Myeloblastin; Chemical synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.12.057

A series of 1,2,3,5-thiatriazolidin-3-one 1,1-dioxide derivatives were synthesized and used to probe the S′ subsites of human neutrophil proteinase 3. The S′ subsites of human neutrophil proteinase 3 (Pr 3) were probed by constructing diverse libraries of compounds based on the 1,2,3,5-thiatriazolidin-3-one 1,1-dioxide using combinational and click chemistry methods. The multiple points of diversity embodied in the heterocyclic scaffold render it well-suited to the exploration of the S′ subsites of Pr 3. Molecular modeling studies suggest that further exploration of the S′ subsites of Pr 3 using the aforementioned heterocyclic scaffold may lead to the identification of highly selective, reversible competitive inhibitors of Pr 3.