Novel Modulators of HDL Metabolism

项目摘要/摘要 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和低水平的高密度脂蛋白胆固醇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(LDL-C)水平显著减少了冠状动脉疾病，但仍有相当大的残余心血管风险，即使极大地降低了低密度脂蛋白-C水平。因此，人们的注意力现在正转向以高密度脂蛋白胆固醇为靶点的策略，作为预防和治疗心血管疾病的辅助治疗。许多研究强调，与低密度脂蛋白胆固醇水平有关的危险因素与高低密度脂蛋白胆固醇水平无关。最近的流行病学数据证实，无论低密度脂蛋白胆固醇水平多么低，低密度脂蛋白胆固醇水平的患者都是早产儿心血管疾病的高危人群。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。这项拟议研究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-C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。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。作为这项第二阶段计划的一部分，我们计划扩大和优化我们的HITS，并利用体内动物模型确认选定的化合物提高高密度脂蛋白-C水平的能力。

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.