6533b82bfe1ef96bd128e0a9
RESEARCH PRODUCT
A frozen analogue approach to aminopyridinylimidazoles leading to novel and promising p38 MAP kinase inhibitors.
Roland SeligDieter SchollmeyerWolfgang AlbrechtStefan LauferVerena SchattelMárcia Inês Goettertsubject
biologyChemistryStereochemistryPyridinesp38 mitogen-activated protein kinasesEntropyImidazolesMolecular ConformationCombinatorial chemistryp38 Mitogen-Activated Protein KinasesMolecular conformationMolecular Docking Simulationchemistry.chemical_compoundStructure-Activity RelationshipPurinesMitogen-activated protein kinaseDrug DesignDrug Discoverybiology.proteinMolecular MedicineStructure–activity relationshipBioisostereBiological evaluationdescription
In this study we report the design, synthesis, and biological evaluation of constrained aminopyridinylimidazoles as p38α MAP kinase inhibitors. The frozen analogue approach focused on the pyridinyl unit, using purine bioisosteres as constrained structure analogues. The identification of the most potent bioisostere was followed by a further derivatization to address hydrophobic region II. In combination with C-2 modifications of the imidazole core, we were able to design highly active inhibitors on the p38α MAP kinase. The inhibitor design presented herein represents a promising and highly efficient advancement of recent stages of development in this class of p38 MAP kinase inhibitors. In combination with the highly flexible synthetic strategy, directions toward further investigations of complex C-5 modifications of diarylimidazoles are indicated.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2012-09-20 | Journal of medicinal chemistry |