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.

项目摘要 该提案描述了一类新的抗血栓和抗炎小的投资 分子称为镰刀疾病（SCD）的分子。 SCD是一组相关的 由血红蛋白的β-珠蛋白亚基突变引起的疾病，导致聚合的聚合 血红蛋白和红细胞的失真引发了一系列危险作用。特别是SCD 患者患有令人衰弱的血管熟悉危机（VOC），涉及捕获“谨慎”的红色血液 小血管中的细胞以及随后的血栓形成和炎症反应，这些反应很痛苦， 危险的。尽管近年来获得了几种新的SCD疗法的批准，但可以急剧的毒品 降低VOC的频率和严重程度尚未确定。帕木素是变构调节剂 蛋白酶激活的受体1（PAR1），并且已经证明了抑制两者激活的能力 在炎症条件下由凝血酶凝血酶驱动的血小板和内皮细胞 （Thrombo-inflammation）。在功能治疗和Erica博士实验室之间的合作伙伴关系中 Sparkenbaugh（北卡罗来纳州的大学，共同投资者），某些Parmodulins已经证明 SCD小鼠模型的效率。在这些结果的基础上，该阶段1项目将识别parmodulins 通过提高效力和口腔活动，并确认其在SCD的小鼠模型中的效率，包括 在SCD患者中施用Hemin以模仿潜在致命的急性胸部综合征。谦虚 将进行药物化学（铅优化）计划，然后进行一系列 体外测定法以识别最有希望的偏头蛋白。这将由药代动力学（PK）完成 研究以识别最适合口服剂量的可生物利用实例。 具体目的：1。合成具有选择性，PAR1的纳摩尔活性的新型丙型蛋白和性能 与慢性口服给药一致。 2。识别口腔活性铅parmodulin并确认其抗血栓形成 和抗炎活动。 3。确认SCD小鼠模型中最佳偏蛋白的体内活性。 除了确认用于治疗SCD的口服活性parmodulins是可行的，该项目还将 建立PK/PD关系和早期剂量回答。成功的结果将证明额外的安全合理性和 未来临床前开发阶段的功效研究，这可能导致预防新疗法 SCD中的VOC，可能用于其他与血管症炎症有关的疾病。