Development of Oral Small Molecule PCSK9 Antagonist

项目摘要/摘要： 心血管疾病(CVD)的流行是一种全球现象，仍然是导致 全世界每年有近1730万人死亡；这一数字预计将增长到 到2030年达到2360万。高胆固醇水平是众所周知的心脏病风险因素。虽然鲜血 可以使用一些上市的药物来降低胆固醇，其中他汀类药物是主要药物， 在服用这些药物的患者中，38%的人正在实现由 国家胆固醇教育计划(NCEP)。此外，纯合子家族性心脏病患者 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不佳， 他们患早产儿心血管疾病的风险很高。这些患者和其他患者将戏剧性地 从积极治疗高胆固醇血症中受益。这项工作的长期目标是发展 降低胆固醇的新型口服生物利用药。我们的治疗目标是蛋白酶原蛋白 转化酶类枯草杆菌毒素9型(PCSK9)。PCSK9控制低密度脂蛋白受体(LDLR)的降解 肝脏因此有助于胆固醇的动态平衡。PCSK9是作为前体蛋白合成的 正在接受处理。分泌的PCSK9与低密度脂蛋白受体(LDLR)结合，并伴随它与 降解途径。为了实现我们的目标，我们鉴定了具有口服活性的纳米分子PCSK9/LDLR 拮抗剂，并在动物模型上验证其疗效。作为这项第二阶段提案的一部分，我们将承诺 在多个动物模型中表征这些化合物以验证概念和 进行安全性评估，以推动先导化合物走向IND使能研究和临床 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.