BACKGROUND The CXCR3 receptor and its three interferon-inducible ligands (CXCL9, CXCL10 and CXCL11) have been implicated as playing a central role in directing a Th1 inflammatory response. Recent studies strongly support that the CXCR3 receptor is a very attractive therapeutic target for treating autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and psoriasis, and to prevent transplant rejection. We describe here the in vitro and in vivo pharmacological characterizations of a novel and potent small molecule CXCR3 antagonist, SCH 546738. RESULTS In this study, we evaluated in vitro pharmacological properties of SCH 546738 by radioligand receptor binding and human activated T cell chemotaxis assays. In vivo efficacy of SCH 546738 was determined by mouse collagen-induced arthritis, rat and mouse experimental autoimmune encephalomyelitis, and rat cardiac transplantation models. We show that SCH 546738 binds to human CXCR3 with a high affinity of 0.4 nM. In addition, SCH 546738 displaces radiolabeled CXCL10 and CXCL11 from human CXCR3 with IC50 ranging from 0.8 to 2.2 nM in a non-competitive manner. SCH 546738 potently and specifically inhibits CXCR3-mediated chemotaxis in human activated T cells with IC90 about 10 nM. SCH 546738 attenuates the disease development in mouse collagen-induced arthritis model. SCH 546738 also significantly reduces disease severity in rat and mouse experimental autoimmune encephalomyelitis models. Furthermore, SCH 546738 alone achieves dose-dependent prolongation of rat cardiac allograft survival. Most significantly, SCH 546738 in combination with CsA supports permanent engraftment. CONCLUSIONS SCH 546738 is a novel, potent and non-competitive small molecule CXCR3 antagonist. It is efficacious in multiple preclinical disease models. These results demonstrate that therapy with CXCR3 antagonists may serve as a new strategy for treatment of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and to prevent transplant rejection.

中文翻译：

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选择性和有效的 CXCR3 拮抗剂 SCH 546738 可减轻自身免疫性疾病的发展并延迟移植排斥。

背景 CXCR3 受体及其三种干扰素诱导型配体（CXCL9、CXCL10 和 CXCL11）被认为在指导 Th1 炎症反应中发挥核心作用。最近的研究强烈支持 CXCR3 受体是治疗自身免疫性疾病（如类风湿性关节炎、多发性硬化症和银屑病）以及预防移植排斥的非常有吸引力的治疗靶点。我们在此描述了一种新型强效小分子 CXCR3 拮抗剂 SCH 546738 的体外和体内药理学特征。结果 在本研究中，我们通过放射性配体受体结合和人类活化 T 细胞趋化性测定评估了 SCH 546738 的体外药理学特性。SCH 546738 的体内功效由小鼠胶原诱导的关节炎确定，大鼠和小鼠实验性自身免疫性脑脊髓炎，以及大鼠心脏移植模型。我们显示 SCH 546738 以 0.4 nM 的高亲和力与人类 CXCR3 结合。此外，SCH 546738 以非竞争性方式取代人 CXCR3 中放射性标记的 CXCL10 和 CXCL11，IC50 范围为 0.8 至 2.2 nM。SCH 546738 有效且特异性地抑制人活化 T 细胞中 CXCR3 介导的趋化性，IC90 约为 10 nM。SCH 546738 减轻小鼠胶原诱导关节炎模型中的疾病发展。SCH 546738 还可显着降低大鼠和小鼠实验性自身免疫性脑脊髓炎模型的疾病严重程度。此外，单独使用 SCH 546738 可实现大鼠心脏同种异体移植存活的剂量依赖性延长。最重要的是，SCH 546738 与 CsA 结合支持永久性移植。结论 SCH 546738 是一种新型、有效且非竞争性的小分子 CXCR3 拮抗剂。它在多种临床前疾病模型中有效。这些结果表明，使用 CXCR3 拮抗剂进行治疗可作为治疗自身免疫性疾病（包括类风湿性关节炎和多发性硬化症）和预防移植排斥的新策略。