Small molecule target for suppression of autoimmunity in rheumatoid arthritis

抑制类风湿性关节炎自身免疫的小分子靶点

• 批准号: 7326950
• 负责人: Scott McNear Thacher
• 金额: $ 25.82万
• 依托单位: ORPHAGEN PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7326950
• 关键词: Adverse effects; Affect; Affinity; Agonist; American; Animal Model; Animals; Autoimmune Diseases; Autoimmunity; Behavior; Bioavailable; Biological Assay; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell physiology; Cells; Class; Collagen; Collagen Arthritis; Collagen Type II; Crohn' s disease; Development; Disease; Dose; Drug Delivery Systems; Drug Design; Drug Kinetics; Evaluation; Family; Genetic; Genetic Transcription; Goals; Grant; Helper-Inducer T-Lymphocyte; Immune; Immune system; Immunization; In Vitro; Inflammation; Inflammatory; Interleukin-17; Investigation; Joints; Knockout Mice; Knowledge; Laboratories; Lead; Ligands; Link; Measures; Mediating; Metabolic; Methotrexate; Modeling; Modification; Multiple Sclerosis; Mus; Nuclear; Nuclear Orphan Receptor; Onset of illness; Orphan; Pain; Pathogenesis; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Positioning Attribute; Predisposition; Property; Public Health; Resistance; Retinoids; Rheumatoid Arthritis; Role; Safety; Sampling; Severities; Severity of illness; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Specificity; Steroids; Surrogate Endpoint; Symptoms; T-Lymphocyte; Testing; Th1 Cells; Therapeutic; Thyroid Gland; Time; Toxic effect; Transfection; Upper arm; Week; analog; autoreactive T cell; base; cell type; cytokine; day; drug mechanism; drug metabolism; human data; human study; immune function; improved; in vivo; infliximab; inhibitor/antagonist; interleukin-23; knockout animal; lymph nodes; novel; receptor; research study; response; small molecule; transcription factor

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.

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，IL-17的靶向缺失或抑制可导致疾病的显着减少。最近发现的 CD4+ T 细胞谱系在功能上不同于众所周知的 CD4+ T 辅助细胞 Th1 和 Th2，表达 IL-17，被称为 RA 动物模型中的严重性。 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，因此申请人已确定Th-17细胞在该疾病的发病机制中可能具有重要作用。 Th-17 细胞形成所需的孤儿受体的小分子配体，并已表明受体拮抗剂可阻止 Th-17 从 na 分化。在这项研究中，我们建议通过鉴定具有良好药代动力学特性的先导化合物来评估这种新型受体作为 RA 药物靶标的效用，并在小鼠胶原诱导性关节炎 (CIA)（一种已建立的 RA 动物模型）中进行测试。 RA。目前的受体拮抗剂不适合进行明确的体内研究，该研究的具体目标包括：（1）与药物化学伙伴合成有希望的药物样药物的类似物，以提高药物的效力并改善代谢稳定性。体内测试； (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；(3) 评估 CIA 中先导化合物在疾病诱导期间和从首次发病时起的作用；大约第 30 天，为了更好地了解这种新化合物的毒性和继发性免疫效应，我们的目标是创造一种全新的口服生物可利用的 RA 药物。阻止主要 T与类固醇、甲氨蝶呤和其他常规用于治疗 RA 的小分子药物相比，它提供了一种有效的治疗方法，副作用减少，治疗用途更广泛。类风湿性关节炎 (RA) 是一种痛苦且致残的疾病，影响着 200 万美国人。针对免疫系统的新药（如恩那西普和英夫利昔单抗）为部分患者（但不是所有患者）提供了缓解，但这些药物却无法缓解疼痛。也有可能限制其使用的严重副作用，拟议的研究将迈出第一步，大力开发一类新型小分子口服生物药物，旨在抑制最近科学证据表明的新型潜在致病性免疫细胞的功能。提示参与 RA 的发病机制。