化学
嗜酸性粒细胞增多
趋化因子
查尔酮
体内
嗜酸性粒细胞
药理学
生物活性
趋化因子受体
体外
受体
免疫学
生物化学
嗜酸性粒细胞增多症
立体化学
医学
生物
哮喘
生物技术
作者
Pierre Regenass,Dayana Abboud,François Daubeuf,Christine Lehalle,Patrick Gizzi,Stéphanie Riché,Muriel Hachet‐Haas,François Rohmer,Vincent Gasparik,Damien Boeglin,Jacques Haiech,Tim Knehans,Didier Rognan,Denis Heissler,Claire Marsol,Pascal Villa,Jean‐Luc Galzi,Marcel Hibert,Nelly Frossard,Dominique Bron
标识
DOI:10.1021/acs.jmedchem.8b00657
摘要
We previously reported Chalcone-4 (1) that binds the chemokine CXCL12, not its cognate receptors CXCR4 or CXCR7, and neutralizes its biological activity. However, this neutraligand suffers from limitations such as poor chemical stability, solubility, and oral activity. Herein, we report on the discovery of pyrimidinone 57 (LIT-927), a novel neutraligand of CXCL12 which displays a higher solubility than 1 and is no longer a Michael acceptor. While both 1 and 57 reduce eosinophil recruitment in a murine model of allergic airway hypereosinophilia, 57 is the only one to display inhibitory activity following oral administration. Thereby, we here describe 57 as the first orally active CXCL12 neutraligand with anti-inflammatory properties. Combined with a high binding selectivity for CXCL12 over other chemokines, 57 represents a powerful pharmacological tool to investigate CXCL12 physiology in vivo and to explore the activity of chemokine neutralization in inflammatory and related diseases.
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