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

描述（由申请人提供）：在我们的SBIR第1阶段研究计划中，我们发现了两种新的ROR？t反向激动剂铅系列，并显示在两种炎症性肠病（IBD）动物模型的疗效。IBD是一种严重的健康负担，仅在美国就降低了140万人的生活质量。Th 17细胞是T辅助细胞的谱系，其最近被鉴定为包括IBD在内的几种人类炎性疾病状态的免疫病理学的关键介质。孤儿核受体T细胞已经被证明是Th 17细胞分化的主控制器。吼？T基因敲除动物对几种自身免疫性疾病具有高度抗性。在健康人中，Th 17细胞主要位于小肠的固有层中。在IBD患者中，这种区室化被打破，Th 17细胞在整个肠道的炎症组织部位迁移和数量扩增。ROR转录活性的拮抗作用？t阻断CD 4 + T细胞向Th 17细胞谱系的分化。因此，ROR？t反向激动剂减少炎症部位的Th 17细胞群。Th 17细胞分泌大量IL-17 A、IL-17 F、IL-22、TNF-？和其他炎性细胞因子。吼？t驱动这些细胞因子的产生，并且已经证明ROR？T反向激动剂减少这些细胞因子从预先存在的Th 17细胞的分泌。因此，小分子反向激动剂的ROR？T将通过减少Th 17细胞群和IL-17 A/F产生来有效治疗IBD。我们发现了新的和有效的ROR？功能性阻断人Th 17细胞离体分化的T反向激动剂。重要的是，我们在两个IBD动物疗效模型中证明，我们最先进的先导化合物显著减轻了疾病。近端靶生物标志物的分析表明，化合物的作用是通过预期的作用机制，ROR的反向激动作用发生的。t.基于SBIR 1期研究的成功，我们提出以下目标：（1）优化新型ROR的药理学性质和口服生物利用度; t反向激动剂使用我们专有的BindingSILIVER药物设计平台，以指导药物化学/测试周期;（2）确定ROR的离体T细胞功能活性？t反向激动剂对人Th 17、Th 1、Th 2和Treg细胞的作用;（3）评价口服生物可利用的ROR？t反向激动剂在IBD动物模型中的应用;（4）评价最先进化合物的安全性/毒性，以提名候选药物用于试验性新药（IND）使能研究。总之，这些研究将为IBD提供口服生物可利用的治疗方法，这将促进随后的人体临床试验。

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.