skepinone-l and dibenzsuberone

The recent disclosure of type I 1/2 inhibitors for p38α MAPK demonstrated how the stabilization of the R-spine can be used as a strategy to greatly increase the target residence time (TRT) of inhibitors. Herein, for the first time, we describe

Topics: Amides; Dibenzocycloheptenes; Drug Design; Drug Stability; Humans; Hydrazones; Microsomes, Liver; Mitogen-Activated Protein Kinase 14; Organoselenium Compounds; Protein Kinase Inhibitors; Structure-Activity Relationship; Time Factors

p38α mitogen-activated protein (MAP) kinase is a main target in drug research concerning inflammatory diseases. Nevertheless, no inhibitor of p38α MAP kinase has been introduced to the market. This might be attributed to the fact that there is no inhibitor which combines outstanding activity in biological systems and selectivity. Herein an approach to the development of such inhibitors on the basis of the highly selective molecular probe Skepinone-L is described. Introduction of a "deep pocket" moiety addressing the DFG motif led to an increased activity of the compounds. Hydrophilic moieties, addressing the solvent-exposed area adjacent to hydrophilic region II, conserved a high activity of the compounds in a whole blood assay. Combined with their outstanding selectivity and low ATP competitiveness, these inhibitors are very interesting candidates for use in biological systems and in therapy.

Topics: Adenosine Triphosphate; Animals; Anti-Inflammatory Agents, Non-Steroidal; Binding Sites; Dibenzocycloheptenes; Hydrophobic and Hydrophilic Interactions; Lipopolysaccharides; Models, Molecular; p38 Mitogen-Activated Protein Kinases; Protein Binding; Solubility; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

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.

Topics: Chemistry Techniques, Synthetic; Dibenzocycloheptenes; Drug Design; Humans; Hydrophobic and Hydrophilic Interactions; Inhibitory Concentration 50; Kinetics; Models, Molecular; p38 Mitogen-Activated Protein Kinases; Protein Conformation; Protein Kinase Inhibitors; Structure-Activity Relationship; Substrate Specificity