Optimization of S1P3 antagonists for fibrotic disease

用于纤维化疾病的 S1P3 拮抗剂的优化

基本信息

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
项目类别：
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

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

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项目摘要

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（通过应用程序提供）：此应用是响应Par-14-279“发现体内化学探针（R01）”，并针对关节炎，肌肉骨骼和皮肤疾病。我们建议将S1PR3验证为关节炎和纤维化的机械靶标。 A类GPCR超家族在药物发现方面的生产力很高。鞘氨酸1-磷酸受体家族由5个GPCR，S1PR1，S1PR2，S1PR3，S1PR4和S1P5组成，并调节了多种生物学反应，包括淋巴细胞运输，血管张力，血管张力，细胞差异和存活。文献和我们的初步数据支持S1P在炎症和纤维化中的作用。 S1PR3的激动剂具有纤维化为包括原发种在内的多种物种的剂量限制毒性。同样，S1PR3可增强对LP的胞质因子的产生，而S1PR3或化学拮抗作用的缺失会钝化细胞因子扩增并抑制纤维化。类风湿关节炎成纤维细胞样性副细胞（RA-FLS）对细胞外基质和炎症细胞因子的扩散，迁移，分泌，被认为是疾病进展的核心，并且依赖于TNF和S1P。 S1PR3表达在RA-FL中升高。 TNF-α诱导的关节炎小鼠中鞘氨酸激酶1的遗传缺失减轻了症状，包括滑膜注射和关节侵蚀。 RA患者滑液中的S1P也升高。我们建议通过鉴定S1PR3受体的潜力，选择性，可生物利用的拮抗剂，并在体外和体内证明概念验证证明，以验证S1PR3作为治疗靶标。这些目标将通过两个特定的目标实现：目标1：开发和优化S1PR3选择性配体具有提高的效力，选择性和药代动力学特性。当前的S1P受体配体将对S1PR3与其他S1P受体家族成员的效力和功能选择性进行优化； S1P1，S1P2，S1P4和S1P5。 S1PR3选择性拮抗剂化合物的物理化学特性，包括微粒体稳定性，可溶性，总极性表面积和药代动力学特性（联合分布）（联合分布）将针对体内使用进行优化。目标2：体外和体内S1PR3拮抗剂的药理和功能表征。该项目将提供新的选择性潜力和可生物利用问题，这些问题专门调节S1PR3信号。这种化合物将促进S1PR3作为类风湿关节炎的药物靶向验证。我们将在体外测试化合物，以抑制细胞增殖，迁移和细胞因子分泌以及体内减少RA症状和tnfdeltaare模型的结果的能力。