title: Heterocycle-based MMP inhibitors with P2' substituents.
abstract: Potent and selective inhibition of matrix metalloproteinases was demonstrated for a series of sulfonamide-based hydroxamic acids. The design of the heterocyclic sulfonamides incorporates a six- or seven-member central ring with a P2' substituent that can be modified. Binding interactions of this substituent at the S2' site are believed to contribute to high inhibitory potency against stromelysin, collagenase-3 and gelatinases A and B, and to provide selectivity against collagenase-1 and matrilysin. An X-ray structure of a stromelysin inhibitor complex was obtained to provide insights into the SAR and selectivity trends observed for the series.
authors.affiliation: Procter and Gamble Pharmaceuticals, Health Care Research Center, Mason, OH 45040, USA. spikul@avalonrx.com
authors.forename: S
authors.initials: S
authors.lastname: Pikul
authors.forename: K M
authors.initials: KM
authors.lastname: Dunham
authors.forename: N G
authors.initials: NG
authors.lastname: Almstead
authors.forename: B
authors.initials: B
authors.lastname: De
authors.forename: M G
authors.initials: MG
authors.lastname: Natchus
authors.forename: Y O
authors.initials: YO
authors.lastname: Taiwo
authors.forename: L E
authors.initials: LE
authors.lastname: Williams
authors.forename: B A
authors.initials: BA
authors.lastname: Hynd
authors.forename: L C
authors.initials: LC
authors.lastname: Hsieh
authors.forename: M J
authors.initials: MJ
authors.lastname: Janusz
authors.forename: F
authors.initials: F
authors.lastname: Gu
authors.forename: G E
authors.initials: GE
authors.lastname: Mieling
mesh_terms: D017364:Collagenases; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D046911:Macromolecular Substances; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D006573:Heterocyclic Compounds, 1-Ring; D046911:Macromolecular Substances; D061965:Matrix Metalloproteinase Inhibitors; D013449:Sulfonamides; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C417249:collagenase 1