Small molecule target for suppression of autoimmunity in rheumatoid arthritis

描述（由申请人提供）：在人类研究中，促炎细胞因子IL-17与关节破坏和类风湿性关节炎（RA）的炎症发病机制有关。靶向缺失或抑制IL-17导致RA动物模型中疾病严重程度的显著降低。最近发现的CD 4 + T细胞谱系在功能上不同于更好地已知的CD 4 + T辅助细胞Th 1和Th 2，其表达IL-17并被称为Th-17。IL-23是Th-17细胞的存活因子。由于IL-23敲除动物对RA的诱导具有抗性，Th-17细胞在疾病的发病机制中可能具有重要意义。申请人已经鉴定了Th-17细胞形成所需的孤儿受体的小分子配体，并且已经表明受体拮抗剂阻断Th-17从幼稚CD 4 + T细胞分化。在这项研究中，我们建议通过确定具有良好药代动力学特性的先导化合物，以评估这种新型受体作为RA药物靶点的效用，用于在小鼠胶原诱导的关节炎（CIA），一种已建立的RA动物模型中进行测试。目前的受体拮抗剂不适用于确定的体内研究。本研究的具体目的将包括：（1）合成类似物，与药物化学伴侣一起有希望的药物样命中物，以增加效力并改善体内测试的代谢稳定性;（2）鉴定CIA引流淋巴结中诱导的主要IL-17+ T细胞类型并表征其对受体配体的反应;以及（3）在疾病诱导期间和从第一症状出现时（约30天）评价先导化合物在CIA中的作用，以便更好地理解药物作用的机制。还将研究这种新化合物类别的毒性和继发性免疫作用。我们的目标是创建一个全新的类口服生物可利用的药物类风湿关节炎，阻断主要的T细胞介导的手臂的免疫发病机制的疾病，从而提供了一个有效的治疗减少副作用和更广泛的治疗效用相比，类固醇，甲氨蝶呤和其他小分子药物常规用于治疗类风湿关节炎。关于与公共卫生的相关性，类风湿性关节炎（RA）是一种影响200万美国人的痛苦和致残性疾病。靶向免疫系统的新药（如恩那西普和英夫利昔单抗）为一些但不是所有患者提供了缓解，但这些药物也有严重的副作用，可能会限制其使用。拟议的研究将迈出第一步，开发一类新的小分子口服生物可利用药物，旨在抑制一种新的潜在致病性免疫细胞的功能，最近的科学证据强烈表明这种免疫细胞参与了RA的发病机制。

DESCRIPTION (provided by applicant): The pro-inflammatory cytokine IL-17 has been implicated in joint destruction and in the inflammatory pathogenesis of rheumatoid arthritis (RA) in human studies. Targeted deletion or inhibition of IL-17 leads to significant reduction in disease severity in animal models of RA. A recently discovered lineage of CD4+ T cells, functionally distinct from the better known CD4+ T helper cells Th1 and Th2, expresses IL-17 and is referred to as Th-17. IL-23 is a survival factor for Th-17 cells. Since IL-23 knockout animals are resistant to induction of RA, Th-17 cells are potentially of major importance in the pathogenesis of the disease. The applicants have identified small molecule ligands to an orphan receptor that is required for the formation of Th-17 cells and have shown that receptor antagonists block Th-17 differentiation from na¿ve CD4+ T cells. In this study, we propose to evaluate the utility of this novel receptor as a drug target for RA by identifying lead compounds with good pharmacokinetic properties for testing in murine collagen-induced arthritis (CIA), an established animal model of RA. Current receptor antagonists are not suitable for definitive in vivo studies. The specific aims of this investigation will include: (1) synthesis of analogs to promising drug-like hits with a medicinal chemistry partner in order to increase potency and improve metabolic stability for in vivo testing; (2) identification of the major IL-17+ T cell types induced in CIA draining lymph nodes and characterization of their response to receptor ligands; and (3) evaluation of lead compound effects in CIA both during disease induction and from the time of first symptoms, about day 30, in order to better understand the mechanism of drug effect. The toxicity and secondary immune effects of this new compound class will be investigated as well. Our goal is to create an entirely new class of orally-bioavailable drugs for RA that blocks the major T cell-mediated arm of immune pathogenesis in the disease, thereby providing an efficacious therapy with reduced side effects and broader therapeutic utility in comparison to steroids, methotrexate and other small molecule drugs routinely used for treatment of RA. With regard to relevance to public health, rheumatoid arthritis (RA) is a painful and crippling disease that affects two million Americans. New drugs that target the immune system (such as entanercept and infliximab) have provided relief for some but not all patients, but the drugs also have serious side effects that may limit their use. The proposed studies would take the first step to develop a new class of small molecule, orally-bioavailable drugs designed to inhibit the function of a novel, potentially pathogenic immune cell that recent scientific evidence strongly suggests is involved in the pathogenesis of RA.