Novel Modulators of HDL Metabolism

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.