HDL Modulators & Plaque Reducers
Cholesterol in your body comes naturally from internal creation or from cholesterol in animal products that you eat. Cholesterol and other fats can't dissolve in the blood. They have to be transported to and from the cells by either low-density lipoprotein (LDL) or high-density lipoprotein (HDL). LDL is commonly known as "bad" cholesterol and can clog your arteries if you have too much of it. HDL is known as the "good" cholesterol and it helps transport the bad cholesterol away from your arteries, thus reducing your risk of a heart attack.1
Atherosclerosis is the process in which deposits of fatty substances, cholesterol, cellular waste products, calcium and other substances build up in the inner lining of an artery, commonly known as plaque buildup. Plaques can grow large enough to significantly reduce the blood flow through an artery, but the most severe damage occurs when they become fragile and subsequently rupture. Plaques that rupture can either cause blood clots to form that can block blood flow or can break off and travel to another part of the body. If either happens and plaque blocks a blood vessel that feeds the heart, it causes a heart attack. If it blocks a blood vessel that feeds the brain, it results in a stroke.2
Arisaph is designing compounds focused on regressing atherosclerosis by raising HDL cholesterol. The research is focused on developing novel therapies that address three targets: 1) apo A-I mimetics; 2) lipase inhibitors; and 3) novel niacin analogs. For the apo A-1 mimetic program, Arisaph innovatively utilized retro-inverso chiral chemistry to produce, reverse D-4F, an orally active peptide that exists in a more optimal configuration than the L-4F mimetic peptide. In a preclinical atherosclerotic animal model, reverse D-4F produced a 46% reduction in plaque and showed anti-inflammatory benefits. Apo A-I mimetic peptides are smaller versions of apolipoprotein A-I, the main protein component of HDL cholesterol. Apo A-I and apo A-I mimetic peptides are under investigation as therapies for atherosclerosis because they have been shown to improve the functionality of HDL cholesterol.
In addition to the rev D-4F lead candidate that has already been produced, Arisaph has designed and synthesized lipase inhibitor drug candidates and novel niacin analogs, both of which operate by modulating HDL cholesterol. This research has been supported by a sponsored research agreement with Abbott Laboratories. Through this research collaboration, Arisaph has been able to leverage its drug discovery platforms to develop differentiated drug candidates and broaden the Company’s therapeutic footprint into cardiovascular disease.
For more information on atherosclerosis, please visit the American Heart Association website at http://www.americanheart.org.
- American Heart Association website. Available at: http://www.americanheart.org/presenter.jhtml?identifier=4488. Accessed April 24, 2008
- American Heart Association website. Available at: http://www.americanheart.org/presenter.jhtml?identifier=4440. Accessed April 24, 2008