title: Inhibition of serine proteases by functionalized sulfonamides coupled to the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold.
abstract: A challenge associated with drug design is the development of selective inhibitors of proteases (serine or cysteine) that exhibit the same primary substrate specificity, that is, show a preference for the same P(1) residue. While these proteases have similar active sites, nevertheless there are subtle differences in their S and S' subsites which can be exploited. We describe herein for the first time the use of functionalized sulfonamides as a design and diversity element which, when coupled to the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold yields potent, time-dependent inhibitors of the serine proteases human leukocyte elastase (HLE), proteinase 3 (PR 3) and cathepsin G(Cat G). Our preliminary findings suggest that (a) appending to the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold recognition and diversity elements that interact with both the S and S' subsites of a target protease may result in optimal enzyme selectivity and potency and, (b) functionalized sulfonamides constitute a powerful design and diversity element with low intrinsic chemical reactivity and potentially wide applicability.
authors.affiliation: Department of Chemistry, Wichita State University, Wichita, KS 67260, USA. groutas@wsuhub.uc.twsu.edu
authors.forename: W C
authors.initials: WC
authors.lastname: Groutas
authors.forename: S
authors.initials: S
authors.lastname: He
authors.forename: R
authors.initials: R
authors.lastname: Kuang
authors.forename: S
authors.initials: S
authors.lastname: Ruan
authors.forename: J
authors.initials: J
authors.lastname: Tu
authors.forename: H K
authors.initials: HK
authors.lastname: Chan
mesh_terms: D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors; D003499:Cyclic S-Oxides / Q000737:chemistry*; D015195:Drug Design; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D053146:Myeloblastin; D012697:Serine Endopeptidases / Q000187:drug effects; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D013844:Thiazoles / Q000737:chemistry*
chemical_list: C428430:1,2,5-thiadiazolidin-3-one 1,1-dioxide; D003499:Cyclic S-Oxides; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D013844:Thiazoles; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D019272:Leukocyte Elastase; D053146:Myeloblastin