Allosteric Modulation of PAR1 for the Treatment of Sickle Cell Disease

PAR1 的变构调节用于治疗镰状细胞病

• 批准号: 10699379
• 负责人: Christopher Dockendorff
• 金额: $ 29.98万
• 依托单位: FUNCTION THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10699379
• 关键词: Activated Partial Thromboplastin Time measurement; Address; Affect; Anti-Inflammatory Agents; Biological Assay; Biological Availability; Biological Markers; Blood; Blood Platelets; Blood Vessels; Cellular Assay; Chronic; Clinical; Coagulation Process; Collaborations; Complement; Cytoprotection; Dangerousness; Diabetes Mellitus; Disease; Disease model; Dose; Drug Kinetics; Endothelial Cells; Endothelium; Enzymes; Erythrocytes; Fibrin fragment D; Frequencies; Functional disorder; Future; G-Protein-Coupled Receptors; GTP-Binding Proteins; Generations; Genetic Diseases; Grant; HMGB1 gene; Hemin; Hemoglobin; Hemostatic function; Hereditary Disease; Human; Incidence; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Investigation; Ischemia; Kidney Diseases; Lead; Ligands; Longevity; Measures; Mediating; Mediator; Microsomes; Modeling; Mus; Mutation; Nerve Degeneration; New Drug Approvals; North Carolina; Oral; Organ; P-Selectin; PAR-1 Receptor; Pain; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phenotype; Platelet aggregation; Polymers; Prevention therapy; Property; Pulmonary Edema; Reperfusion Injury; Research; Research Personnel; Sepsis; Severities; Sickle Cell; Sickle Cell Anemia; Signal Transduction; Signaling Protein; Solubility; Specialist; Stroke; Structural Chemistry; Structure; Testing; Therapeutic; Thrombin; Thrombosis; Validation; Vascular Cell Adhesion Molecule-1; Vascular Diseases; acute chest syndrome; antagonist; beta Globin; beta-arrestin; cell type; commercialization; cytotoxicity; drug discovery; efficacy study; hemoglobin polymer; improved; in vitro Assay; in vivo; inhibitor; innovation; lead candidate; lead optimization; meetings; mortality; mouse model; mutant; nanomolar; novel; novel therapeutics; polymerization; preclinical development; programs; response; safety study; sickling; small molecule; thromboinflammation; thrombotic; vaso-occlusive crisis

PROJECT SUMMARY This proposal describes the investigation of a new class of antithrombotic and anti-inflammatory small molecules called parmodulins for the treatment of sickle cell disease (SCD). SCD is a group of related disorders caused by mutations in the β-globin subunit of hemoglobin that leads to polymerization of hemoglobin and the distortion of red blood cells, initiating a range of dangerous effects. In particular, SCD patients suffer from debilitating vaso-occlusive crises (VOCs), which involve the trapping of “sickled” red blood cells in small blood vessels and subsequent thrombotic and inflammatory responses that are painful and dangerous. Despite the approval of several new SCD therapies in recent years, drugs that can drastically decrease the frequency and severity of VOCs have yet to be identified. Parmodulins are allosteric modulators of protease-activated receptor 1 (PAR1), and have demonstrated the ability to inhibit the activation of both platelets and endothelial cells driven by the coagulation enzyme thrombin under inflammatory conditions (thrombo-inflammation). In a partnership between Function Therapeutics and the lab of Dr. Erica Sparkenbaugh (Univ. of North Carolina, co-investigator), certain parmodulins have already demonstrated efficacy in mouse models of SCD. Building upon these results, this Phase 1 project will identify parmodulins with improved potency and oral activity and confirm their efficacy in mouse models of SCD, including the administration of hemin to mimic the potentially deadly acute chest syndrome in SCD patients. A modest medicinal chemistry (lead optimization) program will be undertaken, followed by a sequence of established in vitro assays to identify the most promising parmodulins. This will be complemented by pharmacokinetic (PK) studies to identify bioavailable examples most suitable for oral dosing. Specific Aims: 1. Synthesize novel parmodulins with selective, nanomolar activity at PAR1, and properties consistent with chronic oral dosing. 2. Identify orally active lead parmodulins and confirm their antithrombotic and anti-inflammatory activities. 3. Confirm in vivo activity of optimal parmodulins in mouse models of SCD. In addition to confirming that orally active parmodulins for the treatment of SCD are feasible, this project will establish PK/PD relationships and early dose-responses. Successful results will justify additional safety and efficacy studies in a future preclinical development phase, which could lead to a new therapy for the prevention of VOCs in SCD, and possibly for other thrombo-inflammation-related disorders.

项目概要 该提案描述了对一类新型抗血栓和抗炎小药物的研究 称为 Parmodulins 的分子用于治疗镰状细胞病 (SCD)。 SCD是一组相关的 由血红蛋白β-珠蛋白亚基突变引起的疾病，导致聚合 血红蛋白和红细胞变形，引发一系列危险影响。特别是，SCD 患者患有使人衰弱的血管闭塞危机（VOC），其中涉及“镰状”红血的滞留 小血管中的细胞以及随后的血栓和炎症反应会带来痛苦和痛苦 危险的。尽管近年来有几种新的 SCD 疗法获得批准，但可以极大地改善 SCD 的药物 减少挥发性有机化合物的频率和严重程度尚未确定。 Parmodulins 是变构调节剂 蛋白酶激活受体 1 (PAR1)，并已证明能够抑制两者的激活 炎症条件下凝血酶驱动的血小板和内皮细胞 （血栓炎症）。 Function Therapeutics 与 Erica 博士的实验室合作 Sparkenbaugh（北卡罗来纳大学，联合研究员），某些 parmodulins 已经证明 在 SCD 小鼠模型中的疗效。基于这些结果，该第一阶段项目将鉴定 Parmodulins 具有改善的效力和口服活性，并证实其在 SCD 小鼠模型中的功效，包括 施用氯化血红素来模拟 SCD 患者可能致命的急性胸部综合征。一个谦虚的 将开展药物化学（先导化合物优化）计划，随后制定一系列 体外测定以确定最有前途的帕莫杜林。这将得到药代动力学 (PK) 的补充 研究以确定最适合口服给药的生物利用度实例。 具体目标： 1. 合成对 PAR1 具有选择性、纳摩尔活性和特性的新型 Parmodulins 与长期口服给药一致。 2. 鉴定口服活性先导parmodulins并确认其抗血栓作用 和抗炎活性。 3. 确认最佳 Parmodulins 在 SCD 小鼠模型中的体内活性。 除了确认口服活性帕莫杜林治疗 SCD 的可行性外，该项目还将 建立 PK/PD 关系和早期剂量反应。成功的结果将证明额外的安全性和 未来临床前开发阶段的功效研究，可能会带来一种新的预防疗法 VOC 在 SCD 中的作用，并可能用于其他血栓炎症相关疾病。