Synthesis and structure–activity relationships of 4-fluorophenyl-imidazole p38α MAPK, CK1δ and JAK2 kinase inhibitors
| Autor: | Jean-Paul G. Seerden, Titia E. Woudenberg-Vrenken, Bas Dros, Richard M. Kellogg, Grietje Molema, Gabriela Leusink-Ionescu, Jan A. A. M. Kamps |
|---|---|
| Přispěvatelé: | Nanotechnology and Biophysics in Medicine (NANOBIOMED), Vascular Ageing Programme (VAP), Groningen Kidney Center (GKC), Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE) |
| Rok vydání: | 2014 |
| Předmět: |
EFFICIENCY
Stereochemistry ANTI-VCAM-1 Carboxylic acid Clinical Biochemistry Aqueous solubility Pharmaceutical Science CK1 delta p38 alpha MAPK CK1 delta JAK2 inhibitors Biochemistry Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Pyridine p38 alpha MAPK Humans Imidazole Tetrazole 4-Fluorophenyl-imidazole Carboxylate Protein Kinase Inhibitors Molecular Biology Alkyne-azide click reaction IN-VIVO chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure JAK2 inhibitors POTENT Kinase ACTIVATED PROTEIN-KINASE Organic Chemistry IMIDAZOLES Janus Kinase 2 Triazoles ENDOTHELIAL-CELLS Phosphonate SAINT-O-SOMES SELECTIVITY chemistry Casein Kinase Idelta DISCOVERY Multicomponent reactions Molecular Medicine Mitogen-Activated Protein Kinases Selectivity |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters, 24(15), 3412-3418. American Chemical Society |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2014.05.080 |
| Popis: | The synthesis and structure-activity relationships of novel 4-(4 '-fluorophenyl)imidazoles as selective p38 alpha MAPK, CK1 delta and JAK2 inhibitors with improved water solubility are described. Microwave-assisted multicomponent reactions afforded 4-fluorophenyl-2,5-disubstituted imidazoles. Carboxylate and phosphonate groups were introduced via 'click' reactions. The kinase selectivity was influenced by the heteroaryl group at imidazole C-5 and the position of a carboxylic acid or tetrazole at imidazole C-2. For example, pyrimidines 15 and 34 inhibited p38 alpha MAPK with IC50 = 250 nM and 96 nM, respectively. Pyridine 3 gave CK1 delta inhibition with IC50 = 89 nM and pyridin-2-one 31 gave JAK2 inhibition with IC50 = 62 nM. (C) 2014 Elsevier Ltd. All rights reserved. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect