2015
Tetrafluorophenoxymethyl ketone cruzain inhibitors with improved pharmacokinetic properties as therapeutic leads for Chagas’ disease
Neitz RJ, Bryant C, Chen S, Gut J, Caselli EH, Ponce S, Chowdhury S, Xu H, Arkin MR, Ellman JA, Renslo AR. Tetrafluorophenoxymethyl ketone cruzain inhibitors with improved pharmacokinetic properties as therapeutic leads for Chagas’ disease. Bioorganic & Medicinal Chemistry Letters 2015, 25: 4834-4837. PMID: 26144347, PMCID: PMC4737481, DOI: 10.1016/j.bmcl.2015.06.066.Peer-Reviewed Original ResearchConceptsCruzain inhibitorsCysteine protease cruzainAnimal modelsSubstrate Activity ScreeningPharmacokinetic propertiesImproved pharmacokinetic propertiesVivo pharmacokinetic propertiesNew chemotherapeutic approachesKetone inhibitorsNew analoguesPromising efficacyReduced lipophilicityOral exposureTherapeutic leadsChemotherapeutic approachesCruzainEfficacious effectsChagas diseaseTherapeutic hypothesesDiseaseNew classInhibitorsTrypanosoma cruziP3 positionPotency
2013
Substrate-Based Fragment Identification for the Development of Selective, Nonpeptidic Inhibitors of Striatal-Enriched Protein Tyrosine Phosphatase
Baguley TD, Xu HC, Chatterjee M, Nairn AC, Lombroso PJ, Ellman JA. Substrate-Based Fragment Identification for the Development of Selective, Nonpeptidic Inhibitors of Striatal-Enriched Protein Tyrosine Phosphatase. Journal Of Medicinal Chemistry 2013, 56: 7636-7650. PMID: 24083656, PMCID: PMC3875168, DOI: 10.1021/jm401037h.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBiphenyl CompoundsBlood-Brain BarrierBoronic AcidsCells, CulturedCerebral CortexHumansNeuronsPermeabilityPhosphorous AcidsProtein Tyrosine Phosphatases, Non-ReceptorRatsRats, Sprague-DawleySmall Molecule LibrariesStereoisomerismStructure-Activity RelationshipSubstrate SpecificityConceptsSubstrate Activity ScreeningProtein tyrosine phosphatase activityProtein tyrosine phosphataseTyrosine phosphatase activityGlutamate receptor internalizationOptimization of fragmentsTyrosine phosphataseDual specificityReceptor internalizationDevelopment of SelectiveSTEP inhibitorPhosphatase activityAlzheimer's diseaseIonotropic glutamate receptorsSubstrate-based approachNonpeptidic inhibitorsPotential targetAD mouse modelDrug discoveryRat cortical neuronsActivity screeningCortical neuronsGlutamate receptorsMouse modelNeuropsychiatric disorders
2007
Substrate activity screening (SAS): a general procedure for the preparation and screening of a fragment-based non-peptidic protease substrate library for inhibitor discovery
Patterson AW, Wood WJ, Ellman JA. Substrate activity screening (SAS): a general procedure for the preparation and screening of a fragment-based non-peptidic protease substrate library for inhibitor discovery. Nature Protocols 2007, 2: 424-433. PMID: 17406604, DOI: 10.1038/nprot.2007.28.Peer-Reviewed Original ResearchConceptsSubstrate Activity ScreeningRapid analog synthesisSolid-phase synthesisActivity screeningSimple fluorescence-based assayFragment-based methodsNon-peptidic inhibitorsN-acyl groupAnalog synthesisInhibitor discoveryFluorescence-based assayWeak binding substratesBinding substrateSubstrate librariesAminocoumarinsProtease substratesSynthesisSubstrateGeneral procedureDirect replacementPharmacophoreNovel substratePreparationConversionCys
2006
Rapid Identification of Potent Nonpeptidic Serine Protease Inhibitors
Salisbury CM, Ellman JA. Rapid Identification of Potent Nonpeptidic Serine Protease Inhibitors. ChemBioChem 2006, 7: 1034-1037. PMID: 16708409, DOI: 10.1002/cbic.200600081.Peer-Reviewed Original Research
2005
Substrate Activity Screening: A Fragment-Based Method for the Rapid Identification of Nonpeptidic Protease Inhibitors
Wood WJ, Patterson AW, Tsuruoka H, Jain RK, Ellman JA. Substrate Activity Screening: A Fragment-Based Method for the Rapid Identification of Nonpeptidic Protease Inhibitors. Journal Of The American Chemical Society 2005, 127: 15521-15527. PMID: 16262416, DOI: 10.1021/ja0547230.Peer-Reviewed Original ResearchConceptsSubstrate Activity ScreeningRapid analog synthesisSimple fluorescence-based assayFragment-based methodsSubstrate-based methodLow molecular weightN-acyl groupAnalog synthesisNonpeptidic inhibitorsFluorescence-based assaySubstrate classesMolecular weightActivity screeningAldehyde inhibitorsAminocoumarinsMultiple distinct classesProtease substratesSAS methodNanomolar affinityCleavage efficiencyCysteine protease cathepsin SSubstrateRapid identificationProtease cathepsin SDirect replacement
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