Journal of Medicinal Chemistry · 2004 · 94 citations · 9 references
PharmacyMedicinal ChemistryPharmacologyDrug DesignDrug DiscoveryStructure-activity RelationshipsEnzyme InhibitionLead Compound DesignLigand BindingLigand-based DesignQuantitative Structure-activity RelationshipsStructure-activity Relationship AnalysisActive Site AnalysisActive Site CharacterizationComparative Oral BioavailabilityCrystal Structure AnalysisMatrix Metalloproteinase InhibitorsProtein Backbone Hydrogen BondsRelative Oral BioavailabilitySelectivity
In this communication we describe the design, synthesis, and evaluation of novel sultam hydroxamates 4 as MMP-2, -9, and -13 inhibitors. Compound 26 was found to be an active inhibitor (MMP-2 IC(50) = 1 nM) with 1000-fold selectivity over MMP-1 and good oral bioavailability (F = 43%) in mouse. An X-ray crystal structure of 26 in MMP-13 confirms the key hydrogen bonds and prime side binding in the active site.
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