Discovery and pharmacological characterization of a novel rodent-active CCR2 antagonist, INCB3344
Discovery and pharmacological characterization of a novel rodent-active CCR2 antagonist, INCB3344
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DOI：
10.4049/jimmunol.175.8.5370
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发表时间：
2005-10-15
影响因子：
4.4
通讯作者：
Vaddi, K
中科院分区：
文献类型：
--
作者：
Brodmerkel, CM;Huber, R;Vaddi, K
本报告描述了INCB 3344，一种新型的，有效的和选择性的小分子拮抗剂的小鼠CCR2受体的表征。迄今为止发现的小分子CCR2拮抗剂缺乏啮齿动物固有的交叉反应性，这排除了对该受体拮抗剂及其治疗相关性的药理学研究。在体外，INCB 3344以纳摩尔效力（IC 50 = 10 nM）抑制CCL 2与小鼠单核细胞的结合，并显示出对CCL 2介导的功能反应（如ERK磷酸化和趋化性）的剂量依赖性抑制，效力相似。针对包括其他CC趋化因子受体的一组G蛋白偶联受体，INCB 3344对CCR2的选择性至少为100倍。INCB 3344在啮齿类动物中具有良好的口服生物利用度和全身暴露，允许进行体内药理学研究。INCB 3344处理导致迟发型超敏反应小鼠模型中巨噬细胞流入的剂量依赖性抑制。组织病理学。对来自迟发型超敏反应模型的组织的分析表明，CCR2的抑制导致组织炎症的显著减少，表明巨噬细胞在基于免疫的炎症反应中起协调作用。这些结果导致了INCB 3344在炎性疾病模型中的研究。我们证明INCB 3344的治疗剂量显著减少了患有实验性自身免疫性脑脊髓炎的小鼠、多发性硬化症模型以及炎性关节炎大鼠模型的疾病。总之，我们提出了第一份报告的药理学特性的选择性，有效的和啮齿动物活性的小分子CCR2拮抗剂。这些数据支持靶向该受体用于治疗慢性炎症性疾病。
This report describes the characterization of INCB3344, a novel, potent and selective small molecule antagonist of the mouse CCR2 receptor. The lack of rodent cross-reactivity inherent in the small molecule CCR2 antagonists discovered to date has precluded pharmacological studies of antagonists of this receptor and its therapeutic relevance. In vitro, INCB3344 inhibits the binding of CCL2 to mouse monocytes with nanomolar potency (IC50 = 10 nM) and displays dose-dependent inhibition of CCL2-mediated functional responses such as ERK phosphorylation and chemotaxis with similar potency. Against a panel of G protein-coupled receptors that includes other CC chemokine receptors, INCB3344 is at least 100-fold selective for CCR2. INCB3344 possesses good oral bioavailability and systemic exposure in rodents that allows in vivo pharmacological studies. INCB3344 treatment results in a dose-dependent inhibition of macrophage influx in a mouse model of delayed-type hypersensitivity. The histopathological. analysis of tissues from the delayed-type hypersensitivity model demonstrates that inhibition of CCR2 leads to a substantial reduction in tissue inflammation, suggesting that macrophages play an orchestrating role in immune-based inflammatory reactions. These results led to the investigation of INCB3344 in inflammatory disease models. We demonstrate that therapeutic dosing of INCB3344 significantly reduces disease in mice subjected to experimental autoimmune encephalomyelitis, a model of multiple sclerosis, as well as a rat model of inflammatory arthritis. In summary, we present the first report on the pharmacological characterization of a selective, potent and rodent-active small molecule CCR2 antagonist. These data support targeting this receptor for the treatment of chronic inflammatory diseases.