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

Abstract

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.

Characteristics of mucin hypersecretion in different inflammatory patterns based on endotypes of chronic rhinosinusitis

“…(3) TNF‐α can significantly up‐regulate the expression of MUC5AC by hCLCA1 46–48 . (4, 5) TNF‐α induces the secretion of MUC5AC and MUC5B by activating two signaling pathways: PLC→DAG→PKC→NO→cGMP→PKG, 54 ERK1/2→p38MAP→MSK1→cAMP 39 . (6) TNF‐α can promote the expression of MUC5AC gene by inducing nuclear translocation of NF‐κB p65 subunit 37 .…”

“… 46 , 47 , 48 (4, 5) TNF‐α induces the secretion of MUC5AC and MUC5B by activating two signaling pathways: PLC→DAG→PKC→NO→cGMP→PKG, 54 ERK1/2→p38MAP→MSK1→cAMP. 39 (6) TNF‐α can promote the expression of MUC5AC gene by inducing nuclear translocation of NF‐κB p65 subunit. 37 (7) TNF‐α can impaired GR‐α nuclear translocation and inhibit the expression of NF‐κB p65, thus inhibiting the expression of MUC1 gene.…”

“… 38 proposed the following mechanism by which TNF‐α might induce MUC5AC gene expression: TNF‐α activates mitogen, mitogen‐ and stress‐activated protein kinase 1(MSK1), cAMP response element‐binding protein, and cAMP response element through ERK1/2 and p38MAP kinases, thereby causing a signaling cascade and inducing Muc5ac gene expression. 39 In human lung mucoepidermoid cancer cell lines, TNF‐α mediates MUC‐2 gene expression via the protein kinase C and tyrosine kinase signal transduction pathways in a concentration‐dependent manner. 40 , 41 However, with the increase in goblet cells, mucus gels are formed in the inflammatory region, and make it difficult for TNF‐α to bind with its receptors.…”

Simple and Efficient Method for Mono‐ and Di‐Amination of Polypyridine N‐Oxides

“…Detailed synthetic methods, optimization studies and preparative procedures together with characterization data of all compounds (MS and NMR spectra) are provided. Additional references have been cited within the Supporting Information [8,15,21–41] …”

Benzotriazoles as Low-Potential Anolytes for Non-aqueous Redox Flow Batteries

“…Compound 5a was synthesized according to a previously described procedure. 42 To a 100 mL flask were added 3bromo-2-nitroaniline (0.868 g, 3 mmol), phenylboronic acid (0.536 g, 4.4 mmol), Pd(PPh 3 ) 4 (0.231 g, 0.2 mmol), and sodium carbonate (1.3 g, 12 mmol). A toluene/ethanol/water mixture (5:1:1, 20 mL) was sparged with nitrogen for 30 min and then added to the flask.…”