Novel Modulators of HDL Metabolism

描述（由申请人提供）：心血管疾病仍然是男性和女性发病和死亡的主要原因，占每年死亡人数的近40%。众所周知，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（HDL-C）是心脏病的危险因素。尽管使用以他汀类药物为主要药物的许多上市药物降低LDL-C水平已显著减少冠状动脉疾病，但即使非常大幅度地降低LDL-C水平，仍存在大量残留的心血管风险。因此，现在的注意力转向靶向HDL作为预防和治疗心血管疾病的辅助治疗策略。许多研究都强调与低HDL水平相关的危险因素与高LDL-C无关。最近的流行病学数据证实，无论LDL水平多低，低HDL-C水平的患者早发心血管疾病的风险都很高。这些患者和其他患者将从积极的低HDL-C治疗中显著获益。这项工作的长期目标是开发增加HDL-C的新药。我们的治疗目标是内皮脂肪酶（EL），它是脂蛋白脂肪酶基因家族的一员，可以水解HDL磷脂。最近的研究表明，在小鼠中抑制EL导致HDL-C水平显著增加。为了实现我们的目标，我们建立了一种灵敏的检测方法来筛选人类EL抑制剂，我们已经确定了筛选命中点。作为I期计划的一部分，我们计划筛选额外的靶点，为所有靶点开发SAR，并通过原位和体内试验确认所选化合物提高HDL-C水平的能力。心脏病是美国男性和女性死亡的主要原因。众所周知，高胆固醇是心脏病的一个危险因素。血液中有两种类型的胆固醇，坏胆固醇（LDL）和好胆固醇（HDL）。为了降低患心脏病的风险，应该降低低密度脂蛋白水平，提高高密度脂蛋白水平。尽管市面上的一些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低的人群。我们的目标是开发提高有益胆固醇水平的新药，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.