Design, synthesis, and biological evaluation of novel disubstituted dibenzosuberones as highly potent and selective inhibitors of p38 mitogen activated protein kinase.
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.
Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-University, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
Solveigh C
SC
Koeberle
Stefan
S
Fischer
Dieter
D
Schollmeyer
Verena
V
Schattel
Christian
C
Grütter
Daniel
D
Rauh
Stefan A
SA
Laufer
D060326:Chemistry Techniques, Synthetic; D003986:Dibenzocycloheptenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
D003986:Dibenzocycloheptenes; D047428:Protein Kinase Inhibitors; C572387:skepinone-L; C011222:dibenzsuberone; D048051:p38 Mitogen-Activated Protein Kinases