化学
C5a受体
过敏毒素
体内
药理学
受体
体外
中性粒细胞
补体系统
趋化性
细胞生物学
生物化学
免疫学
免疫系统
生物技术
生物
作者
Francis Hubler,Dorte Renneberg,Hervé Siendt,Simon Stamm,Kurt Hilpert,Eva Caroff,Stéphane Delahaye,Sylvie Froidevaux,Mark Murphy
标识
DOI:10.1021/acs.jmedchem.3c02375
摘要
C5a is an anaphylatoxin protein produced by the cleavage of the complement system's component C5 protein. It signals through the G-protein-coupled receptor C5a receptor 1 (C5aR1) to induce the chemotaxis of primarily neutrophils and monocytes and the release of inflammatory molecules. A large body of evidence linking C5aR1 signaling to acute and chronic inflammatory disorders has triggered interest in developing potent C5aR antagonists. Herein we report the discovery of new C5aR1 antagonistic chemical classes. Many representatives showed low nanomolar IC50 values in a C5aR1 β-arrestin-2 recruitment assay, inhibiting the migration of human neutrophils toward C5a and the internalization of the receptor in human whole blood. Two leading compounds were characterized further in vivo. Target engagement of the receptor by these two C5aR1 antagonists was demonstrated in vivo. In particular, the inhibition of migration in vitro with the two compounds further translated in a dose-dependent efficacy in a rat model of C5a-induced neutrophilia.
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