Novel Modulators of HDL Metabolism

HDL 代谢的新型调节剂

基本信息

批准号：
7744773
负责人：
Nabil A Elshourbagy
金额：
$ 27.05万
依托单位：
SHIFA BIOMEDICAL CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7744773
关键词：
Accounting Address Affinity Apolipoprotein A-I Asorbicap Attention Binding Biological Assay Blood Cardiovascular Diseases Cardiovascular system Catabolism Cause of Death Cell physiology Cessation of life Cholesterol Clinical Data Coronary Arteriosclerosis Data Databases Degradation Pathway Development Dose Drug or chemical Tissue Distribution Endothelial Cells Endothelium Epidemiology Event Foundations Gene Family Genetic Variation Glycosaminoglycans Goals Heart Diseases High Density Lipoprotein Cholesterol High Density Lipoproteins Homeostasis Human Hydrolysis In Situ Inorganic Sulfates Intervention LDL Cholesterol Lipoproteins Lead Libraries Lipase Lipids Low-Density Lipoproteins Marketing Mediating Metabolism Molecular Weight Morbidity - disease rate Mus Patients Pharmaceutical Preparations Phase Phospholipids Plasma Population Relative (related person)Residual state Risk Risk Factors Screening procedure Site Specificity Structure Testing Transgenic Mice Unspecified or Sulfate Ion Sulfates Woman Work analog base carboxylate cardiovascular risk factor drug development drug market heart disease risk hepatic lipase high risk human LIPG protein improved in vitro Assay in vivo inhibitor/antagonist lipid disorder lipoprotein lipase loss of function meetings member men mortality novel overexpression polysulfated glycosaminoglycan premature prevent public health relevance scaffold therapeutic target

项目摘要

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.

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%。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）是众所周知的心脏病危险因素。尽管使用多种市售药物（其中他汀类药物是主要药物）降低 LDL-C 水平可显着减少冠状动脉疾病，但即使非常积极地降低 LDL-C 水平，仍然存在大量残余心血管风险。因此，现在的注意力正在转向以 HDL 为目标的策略作为预防和治疗心血管疾病的辅助疗法。许多研究强调，与低 HDL 水平相关的危险因素与高 LDL-C 水平无关。最近的流行病学数据证实，无论LDL水平有多低，HDL-C水平低的患者患早发心血管疾病的风险很高。这些患者和其他患者将从低 HDL-C 的积极治疗中获益匪浅。这项工作的长期目标是开发增加 HDL-C 的新药物。我们的治疗靶标是内皮脂肪酶 (EL)，它是脂蛋白脂肪酶基因家族的成员，可水解 HDL 磷脂。最近的研究表明，抑制小鼠的 EL 会导致 HDL-C 水平显着增加。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，并且我们已经确定了筛选结果。作为第一阶段提案的一部分，我们计划筛选其他命中，为所有命中开发 SAR，并使用原位和体内测定确认所选化合物提高 HDL-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死亡的主要原因。高血液胆固醇水平是众所周知的心脏病危险因素。血液中有两种胆固醇，坏胆固醇（LDL）和好胆固醇（HDL）。为了降低患心脏病的风险，应降低低密度脂蛋白水平，并提高高密度脂蛋白水平。尽管可以使用许多市售药物来降低坏胆固醇，但这些药物无法治疗大部分高密度脂蛋白水平较低的人群。我们的目标是开发提高好胆固醇水平的新药，以降低患心脏病的风险。