ABSTRACT
Amino acid-derived phthalimide and saccharin derivatives have been investigated for their inhibitory activity toward the serine proteinases human leukocyte elastase, cathepsin G, and proteinase 3. The saccharin derivatives were found to be effective time-dependent inhibitors of elastase and proteinase 3 (kobs/[I] values ranged between 180 and 3620 M-1 S-1) and showed weak or no inhibition toward cathepsin G. The corresponding phthalimide derivatives were found to be inactive.
Subject(s)
Cathepsins/antagonists & inhibitors , Leukocyte Elastase/antagonists & inhibitors , Phthalimides/pharmacology , Saccharin/analogs & derivatives , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/pharmacology , Amino Acid Sequence , Animals , Binding Sites , Cathepsin G , Drug Design , Humans , Hydrogen Bonding , In Vitro Techniques , Leukocyte Elastase/chemistry , Leukocyte Elastase/genetics , Leukocytes/enzymology , Models, Molecular , Molecular Sequence Data , Myeloblastin , Phthalimides/chemistry , Protein Conformation , Saccharin/chemistry , Saccharin/pharmacology , Serine Proteinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
The results of a structure-activity relationship study focusing on the interaction of a series of phthalimide and saccharin derivatives with leukocyte elastase, cathepsin G and proteinase 3 are described. The phthalimide derivatives were found to be inactive while some of the saccharin derivatives were found to be fair inhibitors of these enzymes.
Subject(s)
Cathepsins/antagonists & inhibitors , Pancreatic Elastase/antagonists & inhibitors , Phthalimides/chemical synthesis , Saccharin/analogs & derivatives , Serine Endopeptidases/drug effects , Cathepsin G , Humans , Leukocyte Elastase , Magnetic Resonance Spectroscopy , Myeloblastin , Phthalimides/chemistry , Phthalimides/pharmacology , Saccharin/chemical synthesis , Saccharin/chemistry , Saccharin/pharmacology , Structure-Activity RelationshipABSTRACT
A series of saccharin derivatives I has been synthesized and evaluated for their inhibitory activity toward human leukocyte elastase and cathepsin G. Most of the compounds were found to be efficient and time-dependent inhibitors of elastase. Inactivated elastase was found to regain its activity almost fully after 24 h (80-90% activity) and the half-lives of reactivation ranged between 12-15 h. Addition of hydroxylamine to fully-inactivated enzyme led to rapid and complete recovery of enzymatic activity. A tentative mechanism of action is proposed on the basis of biochemical and model studies.
Subject(s)
Cathepsins/antagonists & inhibitors , Pancreatic Elastase/antagonists & inhibitors , Saccharin/analogs & derivatives , Cathepsin G , Humans , Leukocyte Elastase , Serine Endopeptidases , Structure-Activity RelationshipSubject(s)
Cystic Fibrosis/drug therapy , Pancreatic Elastase/antagonists & inhibitors , Protease Inhibitors/pharmacology , Amino Acid Sequence , Aspirin/analogs & derivatives , Aspirin/chemical synthesis , Aspirin/pharmacology , Cystic Fibrosis/enzymology , Drug Design , Humans , In Vitro Techniques , Ketoprofen/analogs & derivatives , Ketoprofen/chemical synthesis , Ketoprofen/pharmacology , Kinetics , Leukocytes/enzymology , Molecular Sequence Data , Molecular Structure , Oligopeptides/chemistry , Pancreatic Elastase/blood , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Saccharin/analogs & derivatives , Saccharin/chemical synthesis , Saccharin/pharmacology , Structure-Activity RelationshipABSTRACT
Neutrophil-derived mediators such as, for example, the serine proteinase elastase, cathepsin G and proteinase 3, play a critical role in inflammatory lung disease. This report describes the design, synthesis and in vitro inhibitory activity of some novel mechanism-based inhibitors of human leukocyte elastase and cathepsin G. The design of the inhibitors is based on the Gabriel-Colman rearrangement. The behavior of the synthesized compounds toward elastase and cathepsin G with respect to inhibitory prowess, mode of interaction, specificity, etc., has been found to be dependent on the recognition and reactivity elements present in each inhibitor.
