The Development of RORgt Immunomodulators Targeting the TH17 Axis in IBD- Phase 2

IBD-阶段 2 中针对 TH17 轴的 RORgt 免疫调节剂的开发

• 批准号: 8780723
• 负责人: Gordon Alton
• 金额: $ 82.47万
• 依托单位: VISIONARY PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8780723
• 关键词: Acute; Adverse effects; Adverse event; Agonist; Animal Model; Attenuated; Autoimmune Diseases; B-Lymphocytes; Bioavailable; Biological Assay; Biological Availability; Biological Markers; CD4 Positive T Lymphocytes; Cell Lineage; Cells; Cellular biology; Chemicals; Clinical; Clinical Trials; Colitis; Development; Disease; Disease model; Dose; Drug Design; Drug Kinetics; Gastrointestinal Diseases; Goals; Half-Life; Health; Helper-Inducer T-Lymphocyte; Hour; Human; Immune; Immunomodulators; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inhibitory Concentration 50; Interleukin-17; Investigational Drugs; Lamina Propria; Lead; Ligands; Marketing; Measures; Mediating; Mediator of activation protein; Modality; Modeling; Mus; Nuclear Orphan Receptor; Nuclear Receptors; Oral; Pathology; Patients; Pharmaceutical Chemistry; Pharmacologic Substance; Pharmacology; Phase; Population; Production; Property; Quality of life; Rattus; Regulatory T-Lymphocyte; Research; Resistance; Rodent; Safety; Schedule; Series; Site; Small Business Innovation Research Grant; Small Intestines; Solubility; Specificity; Structure-Activity Relationship; T-Lymphocyte; TNF gene; Testing; Therapeutic; Time; TimeLine; Tissues; Toxic effect; Treatment Efficacy; United States; Work; animal efficacy; base; chemical property; cytokine; dosage; immunopathology; improved; in vivo; innovation; interleukin-22; knockout animal; lead series; novel; palliative; programs; public health relevance; safety study; small molecule; success

DESCRIPTION (provided by applicant): In our SBIR Phase 1 research program we discovered two novel ROR?t inverse agonist lead series and showed efficacy in two animal models of inflammatory bowel disease (IBD). IBD is a significant health burden reducing the quality of life of 1.4 million people in the United States alone. Th17 cells are a lineage of T helper cells that have recently been identified as critical mediators of the immunopathology of several human inflammatory disease states, including IBD. The orphan nuclear receptor ROR?t has been shown to be the master controller of the differentiation of Th17 cells. ROR?t knockout animals are highly resistant to several autoimmune diseases. In healthy people, Th17 cells are chiefly located in the lamina propria of the small intestine. In IBD patients, this compartmentalization breaks down and Th17 cells migrate and expand in number at inflamed tissue sites throughout the gut. Antagonism of the transcriptional activity of ROR?t blocks the differentiation of CD4+ T-cells into the Th17 cell lineage. Thus, ROR?t inverse agonists reduce the Th17 cell population at sites of inflammation. Th17 cells secrete large quantities of IL-17A, IL-17F, IL-22, TNF-? and other inflammatory cytokines. ROR?t drives the production of these cytokines and it has been demonstrated that ROR?t inverse agonists reduce the secretion of these cytokines from pre-existing Th17 cells. Therefore, small molecule inverse agonists of ROR?t will effectively treat IBD by reducing the Th17 cell population and IL-17A/F production. We discovered novel and potent ROR?t inverse agonists that functionally block the ex vivo differentiation of human Th17 cells. Importantly, we demonstrate in two IBD animal efficacy models that our most advanced lead compound significantly attenuates the disease. Analyses of the proximal target biomarkers shows that the compound effects are occurring via the expected mechanism-of-action, inverse agonism of ROR?t. Based on the success of the Phase 1 SBIR work, we propose the following aims: (1) optimize the pharmacological properties and oral bioavailability of novel ROR?t inverse agonists using our proprietary BindingSIGHTS drug design platform to guide a medicinal chemistry/testing cycle; (2) determine the ex vivo T-cell functional activity of ROR?t inverse agonists on human Th17, Th1, Th2 and Treg cells; (3) evaluate the therapeutic efficacy of orally bioavailable ROR?t inverse agonists in animal models of IBD; (4) evaluate the safety/toxicity of the most advanced compounds to nominate candidates for Investigational New Drug (IND) enabling studies. Together, these studies will provide orally bioavailable therapeutics for IBD that will facilitate subsequent human clinical trials.

描述(由申请人提供)：在我们的SBIR第一阶段研究计划中，我们发现了两个新的RoR？T反向激动剂Lead系列，并在两个炎症性肠病(IBD)的动物模型中显示了疗效。IBD是一个严重的健康负担，仅在美国就降低了140万人的生活质量。Th17细胞是辅助性T细胞的一种，最近被确认为包括IBD在内的几种人类炎症性疾病状态免疫病理的关键介质。孤儿核受体ROR？T已被证明是Th17细胞分化的主控者。RoR？t基因敲除动物对几种自身免疫性疾病具有高度抵抗力。在健康人中，Th17细胞主要位于小肠固有层。在IBD患者中，这种分隔被打破，Th17细胞在整个肠道的炎症组织部位迁移和扩张。ROR？T转录活性的拮抗作用阻断了CD4+T细胞向Th17细胞系的分化。因此，RoR？T反向激动剂减少炎症部位的Th17细胞数量。Th17细胞分泌大量IL-17A、IL-17F、IL-22、TNF-？和其他炎性细胞因子。ROR？T驱动这些细胞因子的产生，已有研究表明，ROR？T反向激动剂可减少已存在的Th17细胞分泌这些细胞因子。因此，小分子反向激动剂ROR？T可通过减少Th17细胞数量和IL-17A/F的产生而有效治疗IBD。我们发现了新的和有效的ROR？T反向激动剂，功能上阻止了人Th17细胞的体外分化。重要的是，我们在两个IBD动物疗效模型中证明了我们最先进的先导化合物显著减轻了疾病。对近端靶生物标志物的分析表明，复合效应是通过ROR？T的预期作用机制、反向激动剂发生的。在第一阶段SBIR工作取得成功的基础上，我们提出了以下目标：(1)利用我们的专利BindingSIGHTS药物设计平台优化新型ROR？T反向激动剂的药理性质和口服生物利用度，以指导药物化学/试验周期；(2)测定ROR？T反向激动剂对人Th17、Th1、Th2和Treg细胞的体外T细胞功能活性；(3)在IBD动物模型上评价口服生物可用ROR？T反向激动剂的治疗效果；(4)评估最先进化合物的安全性/毒性，以提名能够进行研究性新药(IND)研究的候选人。总之，这些研究将为IBD提供口服生物可用疗法，这将促进后续的人类临床试验。