Composition contenant au moins un inhibiteur de certaines chimiokines, son procédé d’obtention et son utilisation en dermocosmétique pharmaceutique

La présente invention concerne l'obtention de dérivés de l'acide salicylique OU nicotinique inhibant les chimiokines, leurs préparations et leurs utilisations dans des compositions cosmétiques ou pharmaceutiques destinées à prévenir ou traiter les affections inflammatoires chroniques internes et/ou topiques

A Selective Neutraligand for CXCL12/SDF-1α With Beneficial Regulatory Functions in MRL/Lpr Lupus Prone Mice

Dysregulation of CXCL12/SDF-1-CXCR4/CD184 signaling is associated with inflammatory diseases and notably with systemic lupus erythematosus. Issued from the lead molecule chalcone-4, the first neutraligand of the CXCL12 chemokine, LIT- 927 was recently described as a potent analogue with improved solubility and stability. We aimed to investigate the capacity of LIT-927 to correct immune alterations in lupus-prone MRL/lpr mice and to explore the mechanism of action implemented by this small molecule in this model. We found that in contrast to AMD3100, an antagonist of CXCR4 and agonist of CXCR7, LIT-927 reduces the excessive number of several B/T lymphocyte subsets occurring in the blood of sick MRL/lpr mice (including CD3+/CD4-/CD8-/B220+ double negative T cells). In vitro, LIT-927 downregulated the overexpression of several activation markers on splenic MRL/lpr lymphocytes. It exerted effects on the CXCR4 pathway in MRL/lpr CD4+ T spleen cells. The results underline the importance of the CXCL12/CXCR4 axis in lupus pathophysiology. They indicate that neutralizing CXCL12 by the neutraligand LIT-927 can attenuate hyperactive lymphocytes in lupus. This mode of intervention might represent a novel strategy to control a common pathophysiological mechanism occurring in inflammatory diseases

Pyrimidinone derivatives and uses thereof to neutralize the biological activity of chemokines

A subject of the present invention is a compound having the general formula (I) a pharmaceutically acceptable salt thereof or a tautomeric form thereof, wherein A, B3, B4, B5, Y, X, B1 and B2 are as defined in any one of claims 1 to 10. Another subject of the invention is the compound as defined above for use as a medicament, in particular for preventing and/or treating inflammation and inflammatory diseases, immune and auto-immune diseases, pain related diseases, genetic diseases and/or cancer. L'objet de la présente invention est un composé de la formule générale (I), son sel pharmaceutiquement accepté ou un tautomère de celui-ci, où A, B3, B4, B5, Y, X, B1 et B2 sont tels que définis dans les déclarations 1 à 10. Un autre objet de l'invention est le composé tel que défini ci-dessus pour une utilisation en tant que médicament, en particulier pour prévenir et/ou traiter une inflammation et des maladies inflammatoires, de maladies immunitaires et auto-immunes, de maladies liées à la douleur, de maladies génétiques et/ou du cancer

ACS Med Chem Lett

Chalcone 4 (compound 1) is a small molecule that neutralizes the CXC chemokine CXCL12 and prevents it from acting on the CXCR4 and CXCR7 receptors. To overcome its poor solubility in aqueous buffers, we designed highly soluble analogues of compound 1, phosphate, l-seryl, and sulfate, all inactive by themselves on CXCL12 but when cleaved in vivo into 1, highly active locally at a low dose in a mouse airway hypereosinophilia model

Presentare e comunicare le statistiche: principi, componenti e valutazione della loro qualità

Inhibition of excessive Toll-like receptor 4 (TLR4) signaling is a therapeutic approach pursued for many inflammatory diseases. We report that Mannoside Glycolipid Conjugates (MGCs) selectively blocked TLR4-mediated activation of human monocytes and monocyte-derived dendritic cells (DCs) by lipopolysaccharide (LPS). They potently suppressed pro-inflammatory cytokine secretion and maturation of DCs exposed to LPS, leading to impaired T cell stimulation. MGCs did not interfere with LPS and could act in a delayed manner, hours after LPS stimulation. Their inhibitory action required both the sugar heads and the lipid chain, although the nature of the sugar and the structure of the lipid tail could be modified. They blocked early signaling events at the cell membrane, enhanced internalization of CD14 receptors, and prevented colocalization of CD14 and TLR4, thereby abolishing NF-κB nuclear translocation. When the best lead conjugate was tested in a mouse model of LPS-induced acute lung inflammation, it displayed an anti-inflammatory action by suppressing the recruitment of neutrophils. Thus, MGCs could serve as promising leads for the development of selective TLR4 antagonistic agents for inflammatory diseases

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