Design, synthesis, and biological evaluation of phenylamino-substituted 6,11-dihydro-dibenzo[b,e]oxepin-11-ones and dibenzo[a,d]cycloheptan-5-ones: novel p38 MAP kinase inhibitors.
The pathogenesis of chronic inflammatory diseases is promoted by various pro-inflammatory cytokines. p38 MAP kinase seems to be a valid target as it controls proinflammatory cytokine levels on both transcriptional and translational levels. Starting from benzophenone-type inhibitors, a rigidisation strategy lead to 3-amino-6,11-dihydro-dibenzo[b,e]thiepin-11-one, phenylamino-substituted 6,11-dihydro-dibenzo[b,e]oxepin-11-ones, and dibenzo[a,d]cyclohepten-5-ones. Synthesis, p38 inhibition, and CYP-inhibition of selected compounds are described.
Laufer
Stefan A
SA
Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-Universität, Auf der Morgenstelle 8, 72076 Tübingen, Germany. stefan.laufer@uni-tuebingen.de
Ahrens
Gabriele M
GM
Karcher
Solveigh C
SC
Hering
Jörg S
JS
Niess
Raimund
R
D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D010082:Oxepins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D010082:Oxepins; D047428:Protein Kinase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D048051:p38 Mitogen-Activated Protein Kinases