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.

项目总结