Design, Synthesis and Biological Evaluation of Arylpyridin-2-yl Guanidine Derivatives and Cyclic Mimetics as Novel MSK1 Inhibitors. An Application in an Asthma Model
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 6phenylpyridin‐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 noncytotoxic 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
