Lipid Disorders and Atherosclerosis
Cardiovascular diseases, as a group, are a leading cause of mortality in men and women worldwide. An important pathogenic factor related to heart disease (including stroke) is elevated cholesterol. In the United States alone, it has been estimated that roughly 50 million individuals are candidates for drugs used to lower cholesterol. Due to the vast size of the worldwide market (>$15 billion in 2001), development and commercialization of cholesterol lowering medicines has become a focus of large and small pharmaceuticals companies alike. And while several effective medications are available to lower serum cholesterol, there is a need to develop drugs that help keep serum cholesterol in the normal range by regulating the amount of cholesterol absorbed and stored by the body without interrupting normal pathways of cholesterol synthesis.

Anagen's founder, Dr. Shutsung Liao, and his colleagues at the University of Chicago have been at the forefront of research involving a new target for cholesterol control, namely, orphan nuclear receptors. Of these new receptors, Anagen is focused on the screening and identification of new compounds that activate the liver X receptor or LXR (both and ß sub-types). As depicted in the diagram below, Anagen's lead proprietary compounds (known as LXR ligands) appear to activate several biochemical "switches" that turn on pump-like systems in certain cells (for example, macrophages or "foam cells" in atherosclerotic plaques) to mobilize cholesterol so that it can be removed from the body by the liver and excreted. In addition, these same compounds appear to turn on similar pumps in the intestines that effectively reduce the amount of cholesterol that is absorbed. The diagram below depicts how Anagen's lead LXR compounds under active development are thought to work.

Black arrows point to cellular activation points where Anagen's LXR ligands appear to act. The net result is that intracellular cholesterol is mobilized and removed by the liver in the form of bile acids that are subsequently excreted. The LXR ligands also decrease the net absorption of sterols from the diet. Collectively, these actions reduce circulating levels of cholesterol and decrease unwanted cholesterol accumulation in cells associated with the formation of atherosclerosis. (Graphic redrawn from Lu, T. et al (2001). J. Biol. Chem. 276: 37736)