Novel Modulators of HDL Metabolism

项目概要/摘要 心血管疾病仍然是男女发病和死亡的主要原因，占每年死亡人数的近40%。高水平的LDL-C和低水平的HDL-C是众所周知的心脏病危险因素。尽管使用许多市售药物（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）水平已显著降低冠状动脉疾病，但即使LDL-C水平非常积极地降低，仍存在大量的心血管残余风险。因此，注意力现在转向靶向HDL-C作为预防和治疗心血管疾病的连续治疗的策略。许多研究强调，与低水平HDL-C相关的风险因素独立于高LDL-C。最近的流行病学资料证实，无论LDL-C水平如何低，HDL-C水平低的患者都是早发心血管疾病的高危人群。这些患者和其他患者将从低HDL-C的积极治疗中获益。拟议研究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），脂蛋白脂肪酶基因家族的成员，水解HDL-C磷脂。最近的研究表明，在小鼠中抑制EL导致HDL-C水平显著升高。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增加HDL-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.