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Design, Synthesis and Biological Evaluation of Arylpyridin-2-yl Guanidine Derivatives and Cyclic Mimetics as Novel MSK1 Inhibitors. An Application in an Asthma Model
| Content Provider | MDPI |
|---|---|
| Author | Bollenbach, Maud Nemska, Simona Wagner, Patrick Camelin, Guillaume Daubeuf, François Obrecht, Adeline Villa, Pascal Rognan, Didier Bihel, Frédéric Bourguignon, Jean-Jacques Schmitt, Martine Frossard, Nelly |
| Copyright Year | 2021 |
| Description | Mitogen- and Stress-Activated Kinase 1 (MSK1) is a nuclear kinase, taking part in the activation pathway of the pro-inflammatory transcription factor NF-kB and is demonstrating a therapeutic target potential in inflammatory diseases such as asthma, psoriasis and atherosclerosis. To date, few MSK1 inhibitors were reported. In order to identify new MSK1 inhibitors, a screening of a library of low molecular weight compounds was performed, and the results highlighted the 6-phenylpyridin-2-yl guanidine (compound 1a, IC50~18 µM) as a starting hit for structure-activity relationship study. Derivatives, homologues and rigid mimetics of 1a were designed, and all synthesized compounds were evaluated for their inhibitory activity towards MSK1. Among them, the non-cytotoxic 2-aminobenzimidazole 49d was the most potent at inhibiting significantly: (i) MSK1 activity, (ii) the release of IL-6 in inflammatory conditions in vitro (IC50~2 µM) and (iii) the inflammatory cell recruitment to the airways in a mouse model of asthma. |
| Starting Page | 391 |
| e-ISSN | 14203049 |
| DOI | 10.3390/molecules26020391 |
| Journal | Molecules |
| Issue Number | 2 |
| Volume Number | 26 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2021-01-13 |
| Access Restriction | Open |
| Subject Keyword | Molecules Medicinal Chemistry Pyridine-2-yl Guanidine Msk1 Kinase Inhibitors Inflammation Asthma |
| Content Type | Text |
| Resource Type | Article |
