Novel Modulators of HDL Metabolism

描述(申请人提供)：心血管疾病仍然是男性和女性发病率和死亡率的主要原因，占每年死亡人数的近40%。高水平的低密度脂蛋白胆固醇(LDL-C)和低水平的高密度脂蛋白胆固醇(HDLC)是众所周知的心脏病风险因素。尽管使用一些上市药物(其中他汀类药物是主要药物)降低低密度脂蛋白胆固醇水平显著减少了冠状动脉疾病，但即使极大地降低了低密度脂蛋白胆固醇水平，仍然存在相当大的残余心血管风险。因此，人们的注意力现在正转向以高密度脂蛋白为靶点的策略，作为预防和治疗心血管疾病的辅助治疗。许多研究强调，与低密度脂蛋白水平有关的危险因素与高低密度脂蛋白水平无关。最近的流行病学数据证实，无论低密度脂蛋白水平多么低，低密度脂蛋白胆固醇水平的患者都有较高的早发心血管疾病风险。这些患者和其他患者将从积极的低高密度脂蛋白胆固醇治疗中受益匪浅。这项工作的长期目标是开发提高高密度脂蛋白胆固醇的新药。我们的治疗靶点是内皮脂肪酶(EL)，它是降解高密度脂蛋白磷脂的脂蛋白脂酶基因家族的成员。最近的研究表明，抑制小鼠的EL会导致高密度脂蛋白-C水平的显著增加。为了实现我们的目标，我们建立了一种敏感的检测方法来筛选人EL的抑制剂，并确定了筛选结果。作为这一第一阶段提案的一部分，我们计划筛选更多的Hit，为我们所有的Hit开发SAR，并使用原位和体内分析确认选定化合物提高高密度脂蛋白-C水平的能力。公共卫生相关性：项目叙事心脏病是美国男性和女性的主要死亡原因。血液中的高胆固醇水平是众所周知的心脏病风险因素。血液中有两种胆固醇，坏胆固醇(LDL)和好胆固醇(HDL)。为了降低心脏病的风险，应该降低低密度脂蛋白水平，提高高密度脂蛋白。虽然使用一些市面上销售的药物可以降低坏胆固醇，但这些药物并不能治疗大部分高密度脂蛋白水平较低的人群。我们的目标是开发新的药物，提高有益胆固醇的水平，作为降低心脏病风险的一种手段。

DESCRIPTION (provided by applicant): Cardiovascular disease remains the leading cause of morbidity and mortality for both men and women, accounting for nearly 40% of annual deaths. High levels of low-density lipoprotein cholesterol (LDL-C) and low level of high-density lipoprotein cholesterol (HDL-C) are well-known risk factors for heart disease. Although lowering LDL-C levels using a number of marketed drugs, of which statins are the leading drugs, has significantly reduced coronary artery disease, substantial residual cardiovascular risk remains, even with very aggressive reductions in levels of LDL-C. Accordingly, attention is now shifting toward strategies for targeting HDL as adjunctive therapy to prevent and treat cardiovascular disease. Many studies have emphasized that the risk factor associated with low level of HDL is independent of that of high LDL-C. Recent epidemiological data confirmed that patients with low HDL-C level are at high risk of premature cardiovascular disease no matter how low the LDL level. These and other patients will dramatically benefit from an aggressive treatment of low HDL-C. The long-term goal of this work is to develop novel drugs for increasing HDL-C. Our therapeutic target is endothelial lipase (EL), a member of the lipoprotein lipase gene family that hydrolyzes HDL phospholipids. Recent studies demonstrated that inhibition of EL in mice results in a significant increase in HDL-C levels. To achieve our goal, we have established a sensitive assay to screen for inhibitors of human EL, and we have identified screening hits. As part of this Phase I proposal, we plan to screen for additional hits, develop SAR for all our hits, and confirm the ability of the selected compounds to increase the HDL-C level using in situ and in vivo assays. PUBLIC HEALTH RELEVANCE: Project Narrative Heart disease is the leading cause of death for both men and women in the US. A high blood cholesterol level is a well-known risk factor for heart disease. There are two types of cholesterol in the blood, bad cholesterol (LDL) and good cholesterol (HDL). To lower the risk of heart disease, LDL levels should be lowered and HDL should be raised. Although bad cholesterol can be lowered using a number of marketed drugs, these drugs do not treat a large segment of the population with low HDL levels. Our goal is to develop new drugs that raise the levels of good cholesterol as a means of decreasing the risk of heart disease.