3,4-Diaryl-isoxazoles and -imidazoles as potent dual inhibitors of p38alpha mitogen activated protein kinase and casein kinase 1delta.
In this study, we report on the discovery of isoxazole 1 as a potent dual inhibitor of p38alpha (IC(50) = 0.45 microM) and CK1delta (IC(50) = 0.23 microM). Because only a few effective small molecule inhibitors of CK1 have been described so far, we aimed to develop this structural class toward specific agents. Molecular modeling studies comparing p38alpha/CK1delta suggested an optimization strategy leading to design, synthesis, biological characterization, and SAR of highly potent compounds including 9 (IC(50) p38alpha = 0.006 microM; IC(50) CK1delta = 1.6 microM), 13 (IC(50) p38alpha = 2.52 microM; IC(50) CK1delta = 0.033 microM), 17 (IC(50) p38alpha = 0.019 microM; IC(50) CK1delta = 0.004 microM; IC(50) CK1epsilon = 0.073 microM), and 18 (CKP138) (IC(50) p38alpha = 0.041 microM; IC(50) CK1delta = 0.005 microM; IC(50) CK1epsilon = 0.447 microM) possessing differentiated specificity. Selected compounds were profiled over 76 kinases and evaluation of their cellular efficacy showed 18 (CKP138) to be a highly potent and dual-specific inhibitor of CK1delta and p38alpha.
Peifer
Christian
C
Department of Pharmacy, Eberhard-Karls-University, Auf der Morgenstelle 8, D-72076 Tuebingen, Germany. Peifer@uni-tuebingen.de
Abadleh
Mohammed
M
Bischof
Joachim
J
Hauser
Dominik
D
Schattel
Verena
V
Hirner
Heidrun
H
Knippschild
Uwe
U
Laufer
Stefan
S
D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D048148:Casein Kinase Idelta / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D051381:Rats; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects
D004791:Enzyme Inhibitors; D007093:Imidazoles; D007555:Isoxazoles; C029899:imidazole; D000255:Adenosine Triphosphate; D048148:Casein Kinase Idelta; D048308:Mitogen-Activated Protein Kinase 14