Allosteric Modulation of PAR1 for the Treatment of Sickle Cell Disease

项目摘要 该提案描述了一类新的抗血栓和抗炎小分子药物的研究。 一种称为parmodulins的分子，用于治疗镰状细胞病（SCD）。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， 血红蛋白和红细胞的变形，引发一系列危险的影响。特别是，SCD 患者患有使人衰弱的血管闭塞性危象（VOC），其涉及“镰状”红血的捕获 小血管中的细胞以及随后的血栓形成和炎症反应， 危险了尽管近年来批准了几种新的SCD治疗方法，但可以彻底改变 减少挥发性有机化合物的频率和严重程度还有待确定。Parmodulins是变构调节剂 蛋白酶激活受体1（PAR 1），并已证明有能力抑制激活两者 在炎症条件下由凝血酶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实验室的合作下， Sparkenbaugh（北卡罗来纳州大学，合作研究者），某些parmodulins已经证明， 在SCD小鼠模型中的疗效。在这些结果的基础上，该第1阶段项目将鉴定parmodulins 具有改善的效力和口服活性，并证实了它们在SCD小鼠模型中的功效，包括 施用氯化血红素以模拟SCD患者中潜在致命的急性胸部综合征。适度 药物化学（铅优化）计划将进行，其次是一个序列建立在 体外测定以鉴定最有希望的parmodulins。这将通过药代动力学（PK）来补充 研究以鉴定最适合口服给药的生物可利用的实例。 具体目标：1。合成对PAR 1具有选择性纳摩尔活性的新型parmodulins及其性质 与长期口服给药一致。2.确定口服活性的铅parmodulins和确认其抗血栓形成 和抗炎活性。3.确认最佳parmodulins在SCD小鼠模型中的体内活性。 除了证实口服活性parmodulins治疗SCD是可行的，该项目将 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是合理的， 在未来的临床前开发阶段进行有效性研究，这可能会导致一种新的治疗方法， SCD中的VOC，并可能用于其他血栓炎症相关疾病。

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.