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

基本信息

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
项目类别：
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

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

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项目摘要

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（应用程序提供）：我们发现了PF4的第一个抑制剂，PF4是肝素诱导的血小板减少症（HIT）的病理生理学中心的血小板蛋白。肝素是一种自然疾病的抗凝剂，可防止脉管系统中凝块的形成和现有凝块的扩展，肝素的主要医学应用包括透析，心脏导管插入术和心肺旁路手术。肝素治疗通常是安全有效的。但是，一些患者因免疫反应引起的严重并发症而受到打击，该免疫反应靶向血小板，导致血小板计数低（血小板减少症）。 HIT会增加血管内血凝块形成的风险，并阻止血液流动（血栓形成），当发生血栓形成时被称为HITT。 HITT在用肝素治疗的患者中约有1-3％的患者出现5-10天。受影响的个体患有20％至50％的风险患新的血栓栓塞事件，死亡率约为20％，另外约10％的患者需要截肢或遭受其他重大发病率。当前的命中率治疗依赖于怀疑命中和给药直接凝血酶抑制剂的患者肝素暴露的进化，这些抑制剂具有严重的出血风险。尽管从这些患者中清除了肝素，但他们仍然有重大的血栓形成和死亡的风险。我们发现了一种新颖的方法，可以通过功能激活的PF4四聚体对不活跃的单体和二聚体的稳定进行治疗。 PF4的四聚体形式与肝素结合以形成超大复合物（ULC）。我们最近报告了破坏PF4四聚体的PF4拮抗剂（PF4AS）的鉴定和表征，这是ULC形成的先决条件，并抑制ULC的形成。在此赠款提案中，我们通过设计和准备提高效力，类似或更好的ADMET和类似药物样性能的新类似物来进一步优化当前一系列的PF4四聚体抑制剂（铅复合FC-3157）。利用福克斯·蔡斯化学多样性中心的联合专业知识在医学化学和药物发现方面以及基于命中的方法的纽约血液中心的萨卡斯实验室，我们预计这一II期项目将导致一项或多个PF4首席拮抗剂适用于IV管理下的临床环境中，适用于IND安全评估和最终评估。第一个目的是铅优化合成和医学化学。 AIM 2是对靶向活性的体外测定法评估（抑制PF4四聚体，ULC抑制和抑制细胞激活）。 AIM 3用于评估可接受的ADMET药物价值的类似物，包括：代谢稳定性（微粒体），水溶性，亲脂性，Cypp450抑制作用（7个同工酶最有可能引起暴露可变性和药物可变性）以及IV后的小鼠中的Vivo药物在IV后进行的药物。选定顶部化合物的安全测定包括1）小鼠体内耐受性（MTD），2）HERG和3）AMES评估。 AIM 4涉及评估鼠标命中模型中某些类似物的评估。