Oral PCSK9/LDLR antagonist direction to the clinic

项目总结/摘要 心脏病在美国和世界上已经成为死亡的主要原因超过世纪， 从20世纪初开始在美国，每年约有61万人死于心脏病， 在每4例死亡中。流行病的负担是巨大的; 2016年，心血管疾病（CVD）花费了5550亿美元 到2035年，成本将飙升至1.1万亿美元。高胆固醇水平是众所周知的风险 心脏病的因素。虽然血液胆固醇可以降低使用一些上市的药物， 他汀类药物是主要药物，超过700万患者患有高LDL胆固醇，对 他汀类药物不耐受，另外4 M他汀类药物不耐受和1.3M他汀类药物不耐受是家族性高脂血症（FH）。这些和其他 患者将显著受益于高胆固醇血症的积极治疗。的长期目标 本工作旨在开发新的口服生物可利用的降胆固醇药物。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控制着 低密度脂蛋白受体（LDLR）在肝脏中，从而有助于胆固醇稳态。PCSK 9的合成如下： 一种经过加工的前体蛋白质。分泌的PCSK 9与LDL受体（LDLR）结合， 陪伴它进入降解途径。为了实现我们的目标，我们确定了一个纳摩尔口服活性小 分子PCSK 9/LDLR拮抗剂（P-21），其在喂食高脂饮食的小鼠中显示出突出的效力。LDL- P-21的降胆固醇作用与市售的单克隆抗体一样有效。作为第二阶段的一部分， 根据SBIR提案，我们的目标是将我们的先导化合物（P-21）的开发推进到I期临床试验。 我们的研究将集中在确保P-21坚持作为临床前研究的既定标准。 候选人，并在两种哺乳动物中开展安全性和毒理学研究所需的工作 GLP-IND允许研究申请提交所需的种属。

Project Summary/Abstract Heart disease has been the leading cause of death in the United States and the world for more than a century, ever since the early 1900s. About 610,000 people die of heart disease in the United States every year–that's 1 in every 4 deaths. The epidemic burden is enormous; in 2016, cardiovascular disease (CVD) cost $555 billion in the US alone, and by 2035, the cost will skyrocket to $1.1 trillion. 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, more than 7M patients have high LDL-cholesterol and not responsive to statin, and an additional 4M statin intolerance and 1.3M are familial hypercholesteremic (FH). 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 a nanomolar orally active small molecule PCSK9/LDLR antagonist (P-21) that showed outstanding potency in mice fed high-fat diet. The LDL- cholesterol lowering effect of P-21 is as potent as the marketed monoclonal antibodies. As part of this Phase-II SBIR proposal, our goal is to advance the development of our lead compound (P-21) to Phase-I clinical trial. Our studies will focus on ensuring that P-21 adheres to the set of established criteria as a pre-clinical candidate and on undertaking the work required to obtain the safety and toxicology studies in two mammalian species required for a GLP-IND enabling study application submission.