ABSTRACT
An effort aimed at exploring structural diversity in the N-pyrazole-N'-naphthylurea class of p38 kinase inhibitors led to the synthesis and characterization of N-phenyl-N'-naphthylureas. Examples of these compounds displayed excellent inhibition of TNF-alpha production in vitro, as well as efficacy in a mouse model of lipopolysaccharide induced endotoxemia. In addition, perspective is provided on the role of a sulfonamide functionality in defining inhibitor potency.
Subject(s)
2-Naphthylamine/analogs & derivatives , Protein Kinase Inhibitors/pharmacology , Urea/analogs & derivatives , p38 Mitogen-Activated Protein Kinases/metabolism , 2-Naphthylamine/chemistry , Animals , Chemistry, Organic/methods , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Drug Design , Inhibitory Concentration 50 , Lipopolysaccharides/metabolism , Mice , Models, Chemical , Molecular Structure , Tumor Necrosis Factor-alpha/metabolism , Urea/chemistryABSTRACT
A new class of benzimidazolone p38 MAP kinase inhibitors was discovered through high-throughput screening. X-ray crystallographic data of the lead molecule with p38 were used to design analogues with improved binding affinity and potency in a cell assay of LPS-induced TNFalpha production. Herein, we report the SAR of this new class of p38 inhibitors.
