Effects of structure on inhibitory activity in a series of mechanism-based inhibitors of human neutrophil elastase.
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.
Dou
Dengfeng
D
Department of Chemistry, Wichita State University, Wichita, KS 67260, United States.
He
Guijia
G
Kuang
Rongze
R
Fu
Qingfong
Q
Venkataraman
Radhika
R
Groutas
William C
WC
D003499:Cyclic S-Oxides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053146:Myeloblastin / Q000037:antagonists & inhibitors / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
C428430:1,2,5-thiadiazolidin-3-one 1,1-dioxide; D003499:Cyclic S-Oxides; D011480:Protease Inhibitors; D013844:Thiazoles; D019272:Leukocyte Elastase; D053146:Myeloblastin