title: Implications for selectivity of 3,4-diarylquinolinones as p38alphaMAP kinase inhibitors.
abstract: In this study we report on the specificity profiling of the MAP kinase inhibitors 1, 2, and 3 in a panel of 78 protein kinases including the MAPK isoforms p38(alpha,beta,gamma,delta), JNK1/2/3, and ERK1/2/8 showing 3-(4-fluorophenyl)-4-pyridin-4-ylquinolin-2(1H)-one (1) to be highly selective for p38alphaMAPK with an IC(50) of 1.8 microM. In contrast, besides p38alpha the isoxazoles 2 and 3 significantly inhibited JNK2/3 and further kinases beyond the MAPK family such as PKA, PKD, Lck, and CK1. By using sequence alignment and homology models of different members of the MAPK family the binding mode determining selectivity of 1 for the p38alpha isoform was investigated. For lead optimization of 1 a straightforward tandem-Buchwald-aldol synthetic approach toward the flexible decoration of the quinolin-2(1H)-one scaffold was employed. SAR for derivatives of 1 at the isolated p38alphaMAPK are presented.
authors.affiliation: Department of Pharmacy, Eberhard-Karls-University, Auf derMorgenstelle 8B, D-72076 Tübingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Peifer
authors.forename: Robert
authors.initials: R
authors.lastname: Urich
authors.forename: Verena
authors.initials: V
authors.lastname: Schattel
authors.forename: Mohammed
authors.initials: M
authors.lastname: Abadleh
authors.forename: Marc
authors.initials: M
authors.lastname: Röttig
authors.forename: Oliver
authors.initials: O
authors.lastname: Kohlbacher
authors.forename: Stefan
authors.initials: S
authors.lastname: Laufer
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D007527:Isoenzymes; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D001713:Biphenyl Compounds; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D000255:Adenosine Triphosphate; D048308:Mitogen-Activated Protein Kinase 14; D020928:Mitogen-Activated Protein Kinases