title: Potent inhibition of serine proteases by heterocyclic sulfide derivatives of 1,2,5-thiadiazolidin-3-one 1,1 dioxide.
abstract: The existence of subtle differences in the Sn' subsites of closely-related (chymo)trypsin-like serine proteases, and the fact that the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold docks to the active site of (chymo)trypsin-like enzymes in a substrate-like fashion, suggested that the introduction of recognition elements that can potentially interact with the Sn' subsites of these proteases might provide an effective means for optimizing enzyme potency and selectivity. Accordingly, a series of heterocyclic sulfide derivatives based on the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold (I) was synthesized and the inhibitory activity and selectivity of these compounds toward human leukocyte elastase (HLE), proteinase 3 (PR 3) and cathepsin G (Cat G) were then determined. Compounds with P1 = isobutyl were found to be potent, time-dependent inhibitors of HLE and, to a lesser extent PR 3, while those with P1 = benzyl inactivated Cat G rapidly and irreversibly. This study has demonstrated that 1,2,5-thiadiazolidin-3-one 1,1 dioxide-based heterocyclic sulfides are effective inhibitors of (chymo)trypsin-like serine proteases.
authors.affiliation: Department of Chemistry, Wichita State University, KS 67260, USA.
authors.forename: S
authors.initials: S
authors.lastname: He
authors.forename: R
authors.initials: R
authors.lastname: Kuang
authors.forename: R
authors.initials: R
authors.lastname: Venkataraman
authors.forename: J
authors.initials: J
authors.lastname: Tu
authors.forename: T M
authors.initials: TM
authors.lastname: Truong
authors.forename: H K
authors.initials: HK
authors.lastname: Chan
authors.forename: W C
authors.initials: WC
authors.lastname: Groutas
mesh_terms: D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000187:drug effects; D003499:Cyclic S-Oxides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000187:drug effects; D008958:Models, Molecular; D018716:Molecular Mimicry; D053146:Myeloblastin; D012697:Serine Endopeptidases / Q000187:drug effects / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000502:physiology*; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000494:pharmacology*; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D003499:Cyclic S-Oxides; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D015842:Serine Proteinase Inhibitors; D013440:Sulfides; D013830:Thiadiazoles; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D019272:Leukocyte Elastase; D053146:Myeloblastin