Syntheses and structure-activity relationships for some triazolyl p38 alpha MAPK inhibitors
| Autor: | Bas Dros, Grietje Molema, Gabriela Leusink-Ionescu, Catherine Saccavini, Robin Leguijt, Jean-Paul G. Seerden, Richard M. Kellogg, Jan A. A. M. Kamps, Titia E. Woudenberg-Vrenken, Edith Gelens |
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| Přispěvatelé: | Nanotechnology and Biophysics in Medicine (NANOBIOMED), Vascular Ageing Programme (VAP), Groningen Kidney Center (GKC), Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE) |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
MAPK/ERK pathway
Clinical Biochemistry IMIDAZOLE Pharmaceutical Science Alpha (ethology) p38 Mitogen-Activated Protein Kinases Biochemistry Proinflammatory cytokine Structure-Activity Relationship Downregulation and upregulation DESIGN Drug Discovery Gene expression p38 alpha MAPK inhibitors Human Umbilical Vein Endothelial Cells Humans Cationic liposome Protein Kinase Inhibitors Molecular Biology IC50 COX-2 IL-6 Inflammation IL-6 Chemistry POTENT Organic Chemistry KINASE INHIBITORS Imidazoles Water IN-VITRO Triazoles COX-2 Combinatorial chemistry ENDOTHELIAL-CELLS In vitro DIRECT ALKYNYLATION Solubility PHYSICOCHEMICAL PROPERTIES Liposomes Molecular Medicine CLICK CHEMISTRY Triazole Protein Binding CYCLOADDITION |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters, 24(5), 1352-1357. American Chemical Society |
| ISSN: | 1464-3405 0960-894X |
| DOI: | 10.1016/j.bmcl.2014.01.034 |
| Popis: | The design, synthesis and biological evaluation of novel triazolyl p38 alpha MAPK inhibitors with improved water solubility for formulation in cationic liposomes (SAINT-O-Somes) targeted at diseased endothelial cells is described. Water-solubilizing groups were introduced via a 'click' reaction of functional azides with 2-alkynyl imidazoles and isosteric oxazoles to generate two small libraries of 1,4-disubstituted 1,2,3-triazolyl p38 alpha MAPK inhibitors. Triazoles with low IC50 values and desired physicochemical properties were screened for in vitro downregulation of proinflammatory gene expression and were formulated in SAINT-O-Somes. Triazolyl p38 alpha MAPK inhibitor 88 (IC50 = 0.096 mu M) displayed the most promising in vitro activity. (C) 2014 Elsevier Ltd. All rights reserved. |
| Databáze: | OpenAIRE |
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