SMALL MOLECULE ANTAGONISTS OF PF4 FOR THE TREATMENT AND PREVENTION OF HIT

用于治疗和预防 HIT 的 PF4 小分子拮抗剂

• 批准号: 9330902
• 负责人: Bruce S Sachais
• 金额: $ 96.21万
• 依托单位: FOX CHASE CHEMICAL DIVERSITY CENTER, INC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330902
• 关键词: Acute; Affect; Alpha Cell; Ames Assay; Amputation; Antibodies; Anticoagulants; Applications Grants; Arrhythmia; Binding; Binding Proteins; Biological Assay; Biological Testing; Blood; Blood Platelet Antagonists; Blood Platelets; Blood Vessels; Blood coagulation; Blood flow; Cardiac Catheterization Procedures; Cardiopulmonary Bypass; Caring; Cessation of life; Chemicals; Clinical; Coagulation Process; Collaborations; Complex; Complication; Cytochrome P450; Data; Development; Dialysis procedure; Dimerization; Dose; Drug Interactions; Drug Kinetics; Equilibrium; Evaluation; Event; Excision; Foxes; Functional disorder; Funding; Goals; Hemorrhage; Heparin; Hospitals; In Vitro; Individual; Intellectual Property; Intravenous; Isoenzymes; Laboratories; Lead; Leukocytes; Manuals; Medical; Metabolic; Metabolic Activation; Microsomes; Midazolam; Modeling; Modification; Morbidity - disease rate; Mus; New York; Operative Surgical Procedures; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma Proteins; Platelet Factor 4; Platelet Inhibitors; Preparation; Prevention; Property; Proteins; Reporting; Research; Risk; Safety; Scientist; Series; Small Business Technology Transfer Research; Solubility; Synthesis Chemistry; Testing; Testosterone; Therapeutic Agents; Thrombin; Thrombocytopenia; Thrombosis; analog; aqueous; base; clinical development; commercialization; cytokine; cytotoxicity; data modeling; design; dimer; drug candidate; drug discovery; immunoreaction; improved; in vitro Assay; in vivo; inhibitor/antagonist; iterative design; lipophilicity; medical schools; meetings; monomer; mortality; novel; novel strategies; patch clamp; pre-clinical; predictive modeling; prevent; programs; prototype; public health relevance; public-private partnership; small molecule

 DESCRIPTION (provided by applicant): We have discovered the first-ever inhibitors of PF4, a platelet protein central to the pathophysiology of heparin induced thrombocytopenia (HIT). Heparin is a naturally-occurring anticoagulant that prevents the formation of clots and extension of existing clots within the vasculature, and major medical applications of heparin include dialysis, cardiac catheterization, and cardiopulmonary bypass surgery. Heparin therapy is usually safe and effective; however some patients develop HIT as a serious complication caused by an immunological reaction that targets platelets leading to a low platelet count (thrombocytopenia). HIT increases the risk of blood clots forming within blood vessels and blocking the flow of blood (thrombosis), referred to as HITT when thrombosis occurs. HITT develops in approximately 1-3% of patients treated with heparin for 5-10 days. Affected individuals have a 20-50% risk of developing new thromboembolic events, a mortality rate ~20%, and an additional ~10% of patients require amputations or suffer other major morbidity. Current treatment for HIT relies on elimination of heparin exposure from patients with suspected HIT and administration of direct thrombin inhibitors, which carry a significant risk of bleeding. Despite the removal of heparin from these patients, they remain at significant risk for thrombosis and death. We have discovered a novel approach to the treatment of HIT via the destabilization of the functionally-active PF4 tetramers to inactive monomers and dimers. The tetrameric form of PF4 binds to heparin to form Ultra-large Complexes (ULC). We have recently reported on the identification and characterization of PF4 antagonists (PF4As) that disrupt PF4 tetramerization, which is a prerequisite for ULC formation, and inhibit the formation of ULCs. In this grant proposal further we optimize our current series of PF4 tetramerization inhibitors (lead compound FC-3157) by designing and preparing new analogs that have improved potency and similar or better ADMET and drug-like properties. Using the combined expertise of Fox Chase Chemical Diversity Center, Inc. in medicinal chemistry and drug discovery, and the Sachais Laboratory at the New York Blood Center in HIT-based approaches, we anticipate this Phase II project to result one or more PF4 lead antagonists suitable for IND safety evaluation and ultimate evaluation in a clinical setting under IV administration. The first aim is lead optimization synthetic and medicinal chemistry. Aim 2 is the evaluation of analogs in in vitro assays for targeted activities (inhibition of PF4 tetramerization, ULC inhibition, and inhibition of cellular activation). Aim 3 is for the evaluation of analogs for acceptable ADMET drug values including: metabolic stability (microsomes), aqueous solubility, lipophilicity, CypP450 inhibition (7 isozymes most likely to cause exposure variability and drug-drug interactions), and in vivo pharmacokinetics in mice after IV administration. Safety assays on selected top compounds include 1) in vivo tolerability (MTD) in mice, 2) hERG and 3) Ames evaluation. Aim 4 involves evaluation of select analogs in the mouse HIT model.

 描述（由申请人提供）：我们发现了PF 4的第一种抑制剂，PF 4是肝素诱导的血小板减少症（HIT）病理生理学的核心血小板蛋白。肝素是一种天然存在的抗凝剂，可防止血管系统内血栓的形成和现有血栓的扩展，肝素的主要医疗应用包括透析、心导管插入术和心肺转流手术。肝素治疗通常是安全有效的;然而，一些患者发生HIT，这是由靶向血小板的免疫反应引起的严重并发症，导致血小板计数降低（血小板减少症）。HIT增加了血管内形成血凝块并阻塞血液流动（血栓形成）的风险，当血栓形成发生时称为HITT。在接受肝素治疗5-10天的患者中，约有1-3%发生HITT。受影响的个体有20-50%的风险发生新的血栓栓塞事件，死亡率约为20%，另外约10%的患者需要截肢或患有其他主要疾病。目前对HIT的治疗依赖于消除疑似HIT患者的肝素暴露和直接凝血酶抑制剂的给药，这具有显著的出血风险。尽管从这些患者中移除肝素，但他们仍然存在血栓形成和死亡的显著风险。我们已经发现了一种新的方法来治疗HIT通过功能活性PF 4四聚体的失稳的非活性单体和二聚体。PF 4的四聚体形式与肝素结合以形成超大复合物（ULC）。我们最近报道了PF 4拮抗剂（PF 4As）的鉴定和表征，其破坏PF 4四聚体，这是ULC形成的先决条件，并抑制ULC的形成。在这项资助提案中，我们进一步优化了我们目前的PF 4四聚化抑制剂系列（先导化合物FC-3157），方法是设计和制备新的类似物，这些类似物具有提高的效力和类似或更好的ADMET和药物样特性。利用福克斯大通化学多样性中心，公司的综合专业知识。在药物化学和药物发现方面，以及纽约血液中心的Sachais实验室在基于HIT的方法中，我们预期该II期项目将产生一种或多种PF 4先导拮抗剂，其适用于IV给药的IND安全性评价和临床环境中的最终评价。第一个目标是先导优化合成和药物化学。目的2是在体外测定中评价类似物的靶向活性（抑制PF 4四聚化、ULC抑制和抑制细胞活化）。目的3是评价类似物的可接受ADMET药物价值，包括：代谢稳定性（微粒体）、水溶性、亲脂性、CypP 450抑制（最可能导致暴露变异性和药物相互作用的7种同工酶）以及IV给药后小鼠体内药代动力学。所选顶级化合物的安全性试验包括1）小鼠体内耐受性（MTD），2）hERG和3）艾姆斯评价。目的4涉及在小鼠HIT模型中评价选择的类似物。