Allosteric Modulation of PAR1 for the Treatment of Sickle Cell Disease

项目总结 本提案介绍了一种新型抗血栓和抗炎小分子的研究 用于治疗镰状细胞病(SCD)的分子被称为半调素。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 血红蛋白和红细胞变形，引发一系列危险影响。特别是，SCD 患者遭受衰弱的血管闭塞危象(VOC)的折磨，这涉及到“镰刀状”红血的滞留。 小血管中的细胞和随后的血栓和炎症反应是痛苦的和 危险。尽管近年来批准了几种新的SCD疗法，但可以极大地 降低挥发性有机化合物的频率和严重程度尚未确定。半调素是变构调节剂 蛋白水解酶激活受体1(PAR1)，并已证明有能力抑制两者的激活 炎症条件下凝血酶驱动的血小板和内皮细胞 (血栓-炎症)。在功能治疗公司和埃里卡博士的实验室之间的合作 斯巴肯堡(大学北卡罗来纳州的联合研究员)，某些半调素已经证明 对SCD小鼠模型的疗效观察。在这些结果的基础上，这个第一阶段的项目将确定Parmodins 具有改善的效力和口服活动，并证实其在SCD小鼠模型中的有效性，包括 应用氯化高铁血红素模拟SCD患者潜在致命的急性胸部综合征。谦虚的 将进行药物化学(主导优化)计划，随后将在 体外试验以确定最有希望的半调素。这将得到药代动力学(PK)的补充 研究确定最适合口服给药的生物可用实例。 具体目标：1.合成具有选择性的、在PAR_1处具有纳摩尔活性的新型准分子调节素，并研究其性质 与慢性口服剂量一致。2.鉴定具有口服活性的铅半调素并确认其抗血栓作用 和抗炎活性。3.在SCD小鼠模型中证实最佳半调素的体内活性。 除了确认口服活性帕莫林治疗SCD是可行的外，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疗效研究，这可能导致一种新的预防方法 对于SCD中的VOCs，以及可能对其他血栓炎症相关疾病的影响。

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.