Development of Oral Small Molecule PCSK9 Antagonist

项目概要/摘要： 心血管疾病（CVD）的流行是一种全球现象，仍然是心血管疾病的头号原因。 全世界每年有近1730万人死亡，预计这一数字将增长到 23.6到2030年，亿。高胆固醇水平是众所周知的心脏病危险因素。虽然血 胆固醇可以使用许多市售药物来降低，其中他汀类药物是主要药物， 38%的服用这些药物的患者正在实现低密度脂蛋白胆固醇的目标， 国家胆固醇教育计划（NCEP）。此外，纯合子家族性 胆固醇水平显著升高的高胆固醇血症对目前的药物治疗反应差， 而且患早发心血管疾病的风险很高。这些病人和其他病人将戏剧性地 从高胆固醇血症的积极治疗中获益。这项工作的长期目标是发展 用于降低胆固醇的新型口服生物可利用药物。我们的治疗目标是蛋白酶前蛋白 转化酶枯草杆菌蛋白酶样kexin 9型（PCSK 9）。PCSK 9控制LDL受体（LDLR）的降解， 从而有助于胆固醇的体内平衡。PCSK 9作为前体蛋白合成， 进行加工。分泌的PCSK 9与LDL受体（LDLR）结合，并伴随其与 降解途径为了实现我们的目标，我们鉴定了纳摩尔口服活性小分子PCSK 9/LDLR， 拮抗剂，并证明其在动物模型中的功效。作为第二阶段提案的一部分，我们将 在多个动物模型中表征这些化合物以验证概念所需的所有工作， 进行安全性评估，以推进先导化合物的IND研究和临床 审判

Project Summary/Abstract: The epidemic of cardiovascular disease (CVD) is a global phenomenon that remains the number one cause of death throughout the world, killing nearly 17.3 million people per year; a number that is expected to grow to 23.6 million by 2030. A high cholesterol level is well-known risk factors for heart disease. Although blood cholesterol can be lowered using a number of marketed drugs, of which statins are the leading drugs, only 38% of patients taking these drugs are achieving the low-density lipoprotein cholesterol goals set by the National Cholesterol Education Program (NCEP). Furthermore, patients with homozygous familial hypercholesterolemia who have markedly elevated cholesterol levels respond poorly to current drug therapy, and are at very high risk of premature cardiovascular disease. These and other patients will dramatically benefit from an aggressive treatment of hypercholesterolemia. The long-term goal of this work is to develop novel orally bioavailable drugs for cholesterol lowering. Our therapeutic target is the protease proprotein convertase subtilisin-like kexin type 9 (PCSK9). PCSK9 controls the degradation of the LDL receptor (LDLR) in the liver and thereby contributes to cholesterol homeostasis. PCSK9 is synthesized as a precursor protein that undergoes processing. Secreted PCSK9 binds to the LDL-receptor (LDLR) and chaperones it to the degradation pathway. To achieve our goal, we identified nanomolar orally active small molecule PCSK9/LDLR antagonists and demonstrated its efficacy in animal model. As part of this Phase-II proposal, we will undertake all the work required to characterize these compounds in multiple animal models for the proof of concept and conduct safety assessment in order to advance the lead compound toward IND-enabling studies and clinical trials.