Journal of Medicinal Chemistry · 2002 · 350 citations · 36 references
PharmacyMedicinal ChemistryPharmacologyDrug DesignDrug DiscoveryStructure-activity RelationshipsEnzyme InhibitionLead Compound DesignLigand BindingPharmacophore-based Lead DiscoveryProtein-ligand DockingStructure-activity Relationship AnalysisChemical Structure-activity RelationshipsMitogen-activated Protein Kinase KinaseP38 Mitogen-activated Protein Kinase SignalingProtein Kinase InhibitorsPyrazole ChemistryStructure-based Lead DiscoveryStructure-based Ligand DesignStructure-based Pharmacophore Design
We report on a series of N-pyrazole, N'-aryl ureas and their mode of binding to p38 mitogen activated protein kinase. Importantly, a key binding domain that is distinct from the adenosine 5'-triphoshate (ATP) binding site is exposed when the conserved activation loop, consisting in part of Asp168-Phe169-Gly170, adopts a conformation permitting lipophilic and hydrogen bonding interactions between this class of inhibitors and the protein. We describe the correlation of the structure-activity relationships and crystallographic structures of these inhibitors with p38. In addition, we incorporated another binding pharmacophore that forms a hydrogen bond at the ATP binding site. This modification affords significant improvements in binding, cellular, and in vivo potencies resulting in the selection of 45 (BIRB 796) as a clinical candidate for the treatment of inflammatory diseases.
36
A protein kinase involved in the regulation of inflammatory cytokine biosynthesis
John C. Lee, Jeffrey T. Laydon, Peter McDonnell et al. · Nature · 1994 · 3.3K citations
Ravinder N. Maini, E. William St. Clair, Ferdinand C. Breedveld et al. · The Lancet · 1999 · 2.4K citations