title: Mechanism-based inhibition of human leukocyte elastase and cathepsin G by substituted dihydrouracils.
abstract: A series of dihydrouracil derivatives has been synthesized and investigated for their in vitro inhibitory activity toward human leukocyte elastase (HLE) and cathepsin G (Cath G). Alkyl [sulfonyl(oxy)] uracils 1-2 were found to be efficient, time-dependent inhibitors of elastase (kobs/[I] M-1 s-1 values ranged between 480 and 8110). These compounds formed acyl enzymes that exhibited variable hydrolytic stability which appeared to be dependent on the nature of the R1 group (believed to be accommodated at the primary specificity site, S1). The acyl enzymes formed with cathepsin G deacylated rapidly, leading to a significant regain of enzymatic activity. In sharp contrast, the corresponding phosphorus compounds 3-4 were found to be potent, time-dependent irreversible inhibitors of HLE. Furthermore, the results of the structure-activity relationship studies suggest that the binding modes of compounds 1-2 and 3-4 may be different.
authors.affiliation: Department of Chemistry, Wichita State University, KS 67260.
authors.forename: W C
authors.initials: WC
authors.lastname: Groutas
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.forename: J B
authors.initials: JB
authors.lastname: Epp
authors.forename: R
authors.initials: R
authors.lastname: Venkataraman
authors.forename: J J
authors.initials: JJ
authors.lastname: McClenahan
authors.forename: F
authors.initials: F
authors.lastname: Tagusagawa
mesh_terms: D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D015195:Drug Design; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C007419:dihydrouracil; D014498:Uracil; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase