Optimization of S1P3 antagonists for fibrotic disease

用于纤维化疾病的 S1P3 拮抗剂的优化

• 批准号: 9252358
• 负责人: HUGH ROSEN
• 金额: $ 59.29万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9252358
• 关键词: Agonist; Animal Model; Area; Arthritis; Bioavailable; Biological; Blood Vessels; Cell Differentiation process; Cell Proliferation; Cell Survival; Chemicals; Data; Development; Disease; Disease Progression; Dose-Limiting; Drug Kinetics; Drug Targeting; Extracellular Matrix; Family; Family member; Fibroblasts; Fibrosis; G-Protein-Coupled Receptors; Genetic; Goals; In Vitro; Inflammation; Inflammatory; Joints; Lead; Ligand Binding; Ligands; Literature; Lymphocyte; Microsomes; Modeling; Molecular Bank; Mus; Musculoskeletal Diseases; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Outcome; Patients; Penetration; Pharmaceutical Preparations; Pharmacology; Phase III Clinical Trials; Primates; Production; Property; Rheumatoid Arthritis; Role; SPHK1 enzyme; Series; Signal Transduction; Solubility; Sphingosine-1-Phosphate Receptor; Surface; Symptoms; Synovial Fluid; Synovial joint; Synovitis; TNF gene; Testing; Therapeutic; Toxic effect; Translations; United States National Institutes of Health; Validation; career; cytokine; design; drug discovery; experience; human disease; improved; in vivo; man; migration; professor; programs; public health relevance; receptor; reduce symptoms; response; skin disorder; therapeutic target; trafficking

 DESCRIPTION (provided by applicant): This application is in response to PAR-14-279 "Discovery of in vivo Chemical Probes (R01)" and targets arthritis, musculoskeletal and skin diseases. We propose to validate S1PR3 as a mechanistic target for arthritis and fibrosis. The class A GPCR superfamily is highly productive for drug discovery. The sphingosine- 1-phosphate receptor family consists of 5 GPCRs, S1PR1, S1PR2, S1PR3, S1PR4 and S1P5 and regulates multiple biological responses including lymphocyte trafficking, vascular tone, cell differentiation and survival. The literature and our preliminary data support a role for S1P in inflammation and fibrosis. Agonists of S1PR3 have fibrosis as the dose-limiting toxicity across multiple species including primates. Also, S1PR3 enhances cytokine production in response to LPS, and both deletion of S1PR3 or chemical antagonism blunts cytokine amplification and inhibits fibrosis. The proliferation, migration, secretion of extra-cellular matrix and inflammator cytokines by Rheumatoid arthritis fibroblast-like-synoviocytes (RA-FLS) are thought to be central in disease progression and are dependent on both TNF and S1P. S1PR3 expression is elevated in RA-FLS. Genetic deletion of Sphingosine kinase 1 in the TNF-α-induced arthritis mouse reduced symptoms including synovial inflammation and joint erosion. S1P is also elevated in the synovial fluid of RA patients. We propose to validate S1PR3 as a therapeutic target by identifying potent, selective, bioavailable antagonists of the S1PR3 receptor and demonstrating proof-of-concept in vitro and in vivo. These goals will be approached through two Specific Aims: Aim 1: Develop and optimize S1PR3-selective ligands with improved potency, selectivity and pharmacokinetic properties. Current S1P receptor ligands will be optimized for potency and functional selectivity for S1PR3 versus other S1P receptor family members; S1P1, S1P2, S1P4 and S1P5. Physicochemical properties of S1PR3 selective antagonist compounds including microsome stability, solubility, total polar surface area and pharmacokinetics properties (joint distribution) will be optimized for in vivo use. Aim 2: Pharmacological and functional characterization of S1PR3 antagonists in vitro and in vivo. This project will deliver new selective potent and bioavailable probes that specifically modulate S1PR3 signaling. Such compounds will facilitate validation of S1PR3 as a drug target for rheumatoid arthritis. We will test compounds in vitro for their ability to inhibit cell proliferation, migration and cytokine secretion and in vivo to reduce RA symptoms and outcomes in TNFdeltaARE model.

 描述（由申请人提供）：本申请是对PAR-14-279“体内化学探针（R 01）的发现”的回应，针对关节炎、肌肉骨骼和皮肤疾病。我们建议验证S1 PR 3作为关节炎和纤维化的机制靶点。A类GPCR超家族对于药物发现是高产的。鞘氨醇-1-磷酸受体家族由5个GPCR组成，S1 PR 1、S1 PR 2、S1 PR 3、S1 PR 4和S1 P5，并调节多种生物反应，包括淋巴细胞运输、血管张力、细胞分化和存活。文献和我们的初步数据支持S1 P在炎症和纤维化中的作用。S1 PR 3的激动剂在包括灵长类动物在内的多个物种中具有纤维化作为剂量限制性毒性。此外，S1 PR 3增强响应于LPS的细胞因子产生，并且S1 PR 3的缺失或化学拮抗作用均减弱细胞因子扩增并抑制纤维化。风湿性关节炎成纤维细胞样滑膜细胞（RA FLS）的增殖、迁移、分泌细胞外基质和炎性细胞因子被认为是疾病进展的中心，并且依赖于TNF和S1 P。RA-FLS中S1 PR 3表达升高。在TNF-α诱导的关节炎小鼠中，鞘氨醇激酶1的基因缺失减轻了包括滑膜炎症和关节糜烂在内的症状。S1 P在RA患者的滑液中也升高。我们建议通过鉴定S1 PR 3受体的有效的、选择性的、生物可利用的拮抗剂并在体外和体内证明概念验证来验证S1 PR 3作为治疗靶点。这些目标将通过两个具体目标来实现：目标1：开发和优化具有改进的效力、选择性和药代动力学特性的S1 PR 3选择性配体。目前的S1 P受体配体将针对S1 PR 3相对于其他S1 P受体家族成员S1 P1、S1 P2、S1 P4和S1 P5的效力和功能选择性进行优化。将优化S1 PR 3选择性拮抗剂化合物的物理化学性质，包括微粒体稳定性、溶解度、总极性表面积和药代动力学性质（联合分布）以用于体内使用。目的2：S1 PR 3拮抗剂的体内外药理学和功能表征。该项目将提供新的选择性有效和生物可利用的探针，专门调节S1 PR 3信号。这样的化合物将有助于验证S1 PR 3作为类风湿性关节炎的药物靶标。我们将在TNFDeltaARE模型中测试化合物在体外抑制细胞增殖、迁移和细胞因子分泌的能力以及在体内减少RA症状和结果的能力。