From five- to six-membered rings: 3,4-diarylquinolinone as lead for novel p38MAP kinase inhibitors.
In this study we describe the design, synthesis, and biological evaluation of 3-(4-fluorophenyl)-4-pyridin-4-ylquinoline-2(1H)-one (5) as a new inhibitor of MAPK with a p38alphaMAPK IC50 of 1.8 muM. By keeping the common vicinal pyridine/4-F-phenyl pharmacophore, such as in prototypical imidazole 20 or isoxazole 13 but in 5 connected to the six-membered quinoline core, we were particularly interested in comparing biological activity, details of molecular geometry, and different binding modes of these compounds. Compounds 20 and 13 were active both in the p38alpha- and JNK3-assay, whereas 5 was selective for p38alpha, with no JNK3 inhibition. By comparing the X-ray structures of the compounds, we found a significantly larger distance between the pyridine and the 4-F-phenyl moiety in five-membered core structures relevant for ligand-protein interactions. Molecular modeling studies support the results based on differences in the ATP pockets of p38alpha and JNK3. Because most five-membered core based p38alpha inhibitors show also activity for JNK3, compound 5 is an interesting lead for selective p38alpha inhibitors.
Peifer
Christian
C
Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8/B, D-72076 Tübingen, Germany. christian.peifer@uni-tuebingen.de
Kinkel
Katrin
K
Abadleh
Mohammed
M
Schollmeyer
Dieter
D
Laufer
Stefan
S
D001665:Binding Sites; D018360:Crystallography, X-Ray; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
C519097:3-(4-fluorophenyl)-4-pyridin-4-ylquinoline-2(1H)-one; D006576:Heterocyclic Compounds, 4 or More Rings; D015363:Quinolones; D048057:Mitogen-Activated Protein Kinase 10; D048051:p38 Mitogen-Activated Protein Kinases