Novel Modulators of HDL Metabolism

HDL 代谢的新型调节剂

基本信息

批准号：
8311108
负责人：
Nabil A Elshourbagy
金额：
$ 78.56万
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 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8311108
关键词：
Accounting Active Sites Address Adenoviruses Adverse effects Animal Model Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein A-I Attention Biological Assay Biological Testing Blood Cardiovascular Diseases Cardiovascular system Catabolism Cause of Death Cell physiology Cessation of life Cholesterol Cholesterol Homeostasis Clinical Clinical Data Computer Simulation Coronary Arteriosclerosis Data Degradation Pathway Drug Kinetics Drug or chemical Tissue Distribution Endothelial Cells Epidemiology Event Exhibits Feasibility Studies Future Gene Family Genetic Variation Goals Heart Diseases High Density Lipoprotein Cholesterol High Density Lipoproteins Human In Situ In Vitro Inflammation Mediators Intervention Knock-out LDL Cholesterol Lipoproteins Lead Libraries Lipase Lipids Low-Density Lipoproteins Marketing Mediating Metabolism Morbidity - disease rate Mus Outcome Patients Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phospholipids Plasma Population Property Residual state Risk Risk Factors Safety Site Solubility Specificity Structure Testing Wild Type Mouse Woman abstracting base cardiovascular risk factor chemical synthesis drug development drug market efficacy testing heart disease risk hepatic lipase high risk human LIPG protein improved in vivo inhibitor/antagonist lipid disorder lipoprotein lipase loss of function macrophage meetings member men mortality novel polysulfated glycosaminoglycan potency testing premature prevent protective effect therapeutic target

项目摘要

Project Summary/Abstract 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 LDL-C and low levels of HDL-C are well-known risk factors for heart disease. Although lowering low-density lipoprotein cholesterol (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-C as adjunctive therapy to prevent and treat cardiovascular disease. Many studies have emphasized that the risk factor associated with low levels of HDL-C 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-C level. These and other patients will dramatically benefit from an aggressive treatment of low HDL-C. The long-term goal of the proposed studies 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-C phospholipids. Recent studies demonstrated that inhibition of EL in mice results in a significant increase in HDL-C levels. In Phase I, we have identified selective inhibitors of EL and developed preliminary SAR. As part of this Phase II proposal, we plan to expand and optimize our hits, and confirm the ability of selected compounds to increase the HDL-C level using in vivo animal models.

项目概要/摘要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和低水平的高密度脂蛋白胆固醇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）降低低密度脂蛋白胆固醇 (LDL-C) 水平已显着减少冠状动脉疾病，但即使非常积极地降低 LDL 水平，仍然存在大量残余心血管风险-C。因此，现在的注意力正在转向针对 HDL-C 作为预防和治疗心血管疾病的辅助疗法的策略。许多研究强调，与低 HDL-C 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-C水平有多低，HDL-C水平低的患者发生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。拟议研究的长期目标是开发增加 HDL-C 的新药。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-C 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。在第一阶段，我们已经确定了 EL 的选择性抑制剂并开发了初步的 SAR。作为第二阶段提案的一部分，我们计划扩大和优化我们的命中，并使用体内动物模型确认所选化合物提高 HDL-C 水平的能力。