6533b7d9fe1ef96bd126ce75
RESEARCH PRODUCT
Design, synthesis, and biological evaluation of novel disubstituted dibenzosuberones as highly potent and selective inhibitors of p38 mitogen activated protein kinase.
Solveigh C. KoeberleVerena SchattelDaniel RauhChristian GrütterStefan FischerDieter SchollmeyerStefan Laufersubject
Models MolecularProtein Conformationp38 mitogen-activated protein kinasesmedicine.medical_treatmentChemistry Techniques SyntheticDibenzocycloheptenesp38 Mitogen-Activated Protein KinasesSubstrate SpecificityInhibitory Concentration 50Structure-Activity RelationshipProtein structureDrug DiscoverymedicinePotencyStructure–activity relationshipHumansProtein Kinase InhibitorsbiologyKinaseChemistryCombinatorial chemistryKineticsCytokineBiochemistryMitogen-activated protein kinaseDrug Designbiology.proteinMolecular MedicineSelectivityHydrophobic and Hydrophilic Interactionsdescription
Synthesis, biological testing, structure-activity relationships (SARs), and selectivity of novel disubstituted dibenzosuberone derivatives as p38 MAP kinase inhibitors are described. Hydrophilic moieties were introduced at the 7-, 8-, and 9-position of the 2-phenylamino-dibenzosuberones, improving physicochemical properties as well as potency. Extremely potent inhibitors were obtained, with half-maximal inhibitory concentration (IC(50)) values in the low nM range in a whole blood assay measuring the inhibition of cytokine release. The high potency of the target compounds together with the outstanding selectivity of this novel class of compounds toward p38 mitogen activated protein (MAP) kinase as compared to other kinases indicate them to be most applicable as tools in pharmacological research and eventually they may foster a new generation of anti-inflammatory drugs.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2012-06-09 | Journal of medicinal chemistry |