Mechanism-based inhibitors of serine proteases with high selectivity through optimization of S′ subsite binding

• Published in: Bioorganic & medicinal chemistry 2009-05, Vol.17 (10), p.3536-3542
• Main Authors: Li, Yi, Dou, Dengfeng, He, Guijia, Lushington, Gerald H., Groutas, William C.
• Format: Article
• Language: English
• Subjects: Binding Sites; Biological and medical sciences; Computer Simulation; Drug Design; Humans; Inhibitors; Leukocyte Elastase - antagonists & inhibitors; Leukocyte Elastase - metabolism; Medical sciences; Miscellaneous; Myeloblastin - antagonists & inhibitors; Myeloblastin - metabolism; Pharmacology. Drug treatments; Proteases; Protein Structure, Tertiary; Serine; Serine Endopeptidases - chemistry; Serine Endopeptidases - metabolism; Serine Proteinase Inhibitors - chemical synthesis; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacology; Structure-Activity Relationship; Substrate Specificity; Thiadiazoles - chemical synthesis; Thiadiazoles - chemistry; Thiadiazoles - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.04.011

A series of 1,2,5-thiadiazolidin-3-one 1,1-dioxide derivatives were found to be potent and selective inhibitors of human neutrophil elastase but not proteinase 3. A series of mechanism-based inhibitors designed to interact with the S′ subsites of serine proteases was synthesized and their inhibitory activity toward the closely-related serine proteases human neutrophil elastase (HNE) and proteinase 3 (PR 3) was investigated. The compounds were found to be time-dependent inhibitors of HNE and were devoid of any inhibitory activity toward PR 3. The results suggest that highly selective inhibitors of serine proteases whose primary substrate specificity and active sites are similar can be identified by exploiting differences in their S′ subsites. The best inhibitor (compound 16) had a k inact/ K I value of 4580 M −1 s −1.