期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 275, 期 25, 页码 19000-19008出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M001222200
关键词
-
The CC chemokine receptor-1 (CCR1) is a prime therapeutic target for treating autoimmune diseases. Through high capacity screening followed by chemical optimization, we identified a novel non-peptide CCR1 antagonist, R-N-[5-chloro-2-[2-[4-[(4-fluorophenyl)methyl]-2-methyl-1-piperazinyl]-2-oxoethoxy]phenyl]urea hydrochloric acid salt (BX 471), Competition binding studies revealed that BX 471 was able to displace the CCR1 ligands macrophage inflammatory protein-1 alpha (MIP-1 alpha), RANTES, and monocyte chemotactic protein-3 (MCP-3) with high affinity (K-i ranged from 1 nM to 5.5 nM), BX 471 was a potent functional antagonist based on its ability to inhibit a number of CCR1-mediated effects including Ca2+ mobilization, increase in extracellular acidification rate, CD11b expression, and leukocyte migration, BX 471 demonstrated a greater than 10,000-fold selectivity for CCR1 compared with 28 G-protein-coupled receptors, Pharmacokinetic studies demonstrated that BX 471 was orally active with a bioavailability of 60% in dogs. Furthermore, BX 471 effectively reduces disease in a rat experimental allergic encephalomyelitis model of multiple sclerosis, This study is the first to demonstrate that a non-peptide chemokine receptor antagonist is efficacious in an animal model of an autoimmune disease. In summary, we have identified a potent, selective, and orally available CCR1 antagonist that may be useful in the treatment of chronic inflammatory diseases.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据