Abstract
Described are the acylation binding of trans-lactam 1 to porcine pancreatic elastase, the selection of the SO2Me activating group for the lactam N which also confers metabolic stability in hamster liver microsomes, the introduction of aqueous solubility through the piperidine salt 9, the in vivo oral activity of 9 and its bioavailability, and the introduction of 9 as an intracellular neutrophil elastase inhibitor.
MeSH terms
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Acylation
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Administration, Oral
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Animals
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Binding Sites
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Cricetinae
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Crystallography, X-Ray
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology
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Humans
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Inhibitory Concentration 50
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Lactams / chemistry
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Lactams / pharmacokinetics*
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Lactams / pharmacology
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Leukocyte Elastase / antagonists & inhibitors*
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Models, Molecular
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Neutrophils / drug effects*
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Neutrophils / enzymology
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Pancreas / enzymology
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Protein Binding
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Pyrrolidines / chemistry
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Pyrrolidines / pharmacokinetics
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Pyrrolidines / pharmacology
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Solubility
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Structure-Activity Relationship
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Swine
Substances
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Enzyme Inhibitors
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Lactams
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Pyrrolidines
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Leukocyte Elastase