Jenh Chung-Her, Cox Mary Ann, Cui Long, Reich Eva-Pia, Sullivan Lee, Chen Shu-Cheng, Kinsley David, Qian Shiguang, Kim Seong Heon, Rosenblum Stuart, Kozlowski Joseph, Fine Jay S, Zavodny Paul J, Lundell Daniel
Department of Respiratory and Immunology, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
BMC Immunol. 2012 Jan 10;13:2. doi: 10.1186/1471-2172-13-2.
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.
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.
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.
CXCR3受体及其三种干扰素诱导配体（CXCL9、CXCL10和CXCL11）被认为在引导Th1炎症反应中起核心作用。最近的研究有力地支持了CXCR3受体是治疗自身免疫性疾病（如类风湿性关节炎、多发性硬化症和牛皮癣）以及预防移植排斥反应的一个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性。
在本研究中，我们通过放射性配体受体结合和人活化T细胞趋化性测定评估了SCH 546738的体外药理学特性。通过小鼠胶原诱导性关节炎、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确定了SCH 546738的体内疗效。我们表明，SCH 546738以0.4 nM的高亲和力与人CXCR3结合。此外，SCH 546738以非竞争性方式从人CXCR3上置换放射性标记的CXCL10和CXCL11，IC50范围为0.8至2.2 nM。SCH 546738以约10 nM的IC90有效且特异性地抑制人活化T细胞中CXCR3介导的趋化性。SCH 546738减轻小鼠胶原诱导性关节炎模型中的疾病发展。SCH 546738还显著降低大鼠和小鼠实验性自身免疫性脑脊髓炎模型中的疾病严重程度。此外，单独使用SCH 546738可实现大鼠心脏同种异体移植存活时间的剂量依赖性延长。最显著的是，SCH 546738与环孢素A联合使用可支持永久植入。
SCH 546738是一种新型、强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，用CXCR3拮抗剂进行治疗可能成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）以及预防移植排斥反应的一种新策略。
