Effects of structure on inhibitory activity in a series of mechanism-based inhibitors of human neutrophil elastase

• Published in: Bioorganic & medicinal chemistry 2010-09, Vol.18 (18), p.6646-6650
• Main Authors: Dou, Dengfeng, He, Guijia, Kuang, Rongze, Fu, Qingfong, Venkataraman, Radhika, Groutas, William C.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cyclic S-Oxides - chemical synthesis; Cyclic S-Oxides - chemistry; Cyclic S-Oxides - pharmacology; Elastase; Humans; Inhibitors; Kinetics; Leukocyte Elastase - antagonists & inhibitors; Leukocyte Elastase - metabolism; Medical sciences; Myeloblastin - antagonists & inhibitors; Myeloblastin - metabolism; Neutrophil elastase; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.07.071

A series of compounds based on the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold were synthesized and used to probe the S′ subsites of human neutrophil elastase and proteinase 3. A structurally-diverse series of carboxylate derivatives based on the 1,2,5-thiadiazolidin-one 1,1 dioxide scaffold were synthesized and used to probe the S′ subsites of human neutrophil elastase (HNE) and neutrophil proteinase 3 (Pr 3). Several compounds are potent inhibitors of HNE but devoid of inhibitory activity toward Pr 3, suggesting that the S′ subsites of HNE exhibit significant plasticity and can, unlike Pr 3, tolerate various large hydrophobic groups. The results provide a promising framework for the design of highly selective inhibitors of the two enzymes.