Technology and Products

Cardiovascular Disease

Coronary heart disease (CHD) is currently managed by various drug therapies that include HMG-CoA reductase inhibitors (collectively known as statins), as well as other compounds such as fibrates, bile acid sequestrants, niacin and the like. Of these drugs, statins are the most prescribed because they are effective in lowering total cholesterol and low-density lipoprotein cholesterol (LDL-C). It has been found that statins have a small to moderate effect on triglycerides and a minimal effect at raising high-density lipoprotein cholesterol (HDL-C) levels, the so-called "good cholesterol". While the National Cholesterol Education Program (NCEP) treatment guidelines recognize LDL-C as the primary target of therapy for prevention, it now focuses on HDL-C levels as a major risk factor. Moreover, the Adult Treatment Panel (ATP) of NCEP has now raised the HDL-C lower limit from 35 mg/dL to 40 mg/dL.

Fibrates were the first ligands implicated during the search for peroxisome proliferator-activated receptors (PPARs); PPARs are intimately associated with cellular metabolism (carbohydrate, lipid and protein) and cell differentiation. When it turned out that PPARs played a much more versatile role in biology, the agents were in turn termed "PPAR ligands" or “PPAR agonists”.

There are 3 distinct families of PPAR receptors ( α, γ, and σ). PPAR-α primarily modulate lipid metabolism, lowering serum triglycerides levels and increasing HDL levels. Fenofibrate and gemfibrozil are relatively weak ligands for the PPAR-α receptor; for this reason active research was initiated to develop more potent and selective agents. However, none of the more potent PPAR-α agonists has achieved regulatory approval and more than 50 PPAR agonists have been discontinued due to various types of toxicity, e.g., "cardiac, skeletal muscle, renal, and bone marrow. The casualties include ragaglitazar, reglitazar and, most recently, MK-767, due to edema, raised levels of hepatic enzymes and tumors in rodents.

Fenofibrate increases plasma HDL by directly activating five key genes involved in HDL metabolism: apolipoprotein A-I, apolipoprotein A-II, lipoprotein lipase, and ATP-binding cassette transporter-I (ABC-I; HDL receptors). Recently, fenofibrate has been found to be a more potent inhibitor of scavenger receptor class-B type-I (SR-BI) than activator or agonist of PPAR-α (Journal of Lipid Research. 2007. 48: 1832-1845). This is a significant discovery because this now shifts the mode of action of fenofibrate from an agonist to an inhibitor. Agonists tend to be more general and activate more than one receptor or enzyme pathway, which can give side effects. Fenofibrate is a potent (IC50 ~1 muM) direct inhibitor of SRBI, which represents a novel strategy for raising HDL. SR-BI binds HDL primarily via HDL's main protein component (apolipoprotein A-I), the HDL-cholesterol complex (primarily cholesteryl ester but also unesterified cholesterol) is transferred to the cells, and then the lipid-depleted HDL particles dissociate and reenter the extracellular space. SR-BI can also mediate unesterified cholesterol efflux from cells to HDL.

Fibrates have been used for the treatment of hypertriglyceridemia or mixed hyperlipidemia for more than 30 years. The marketed fibrates include: gemfibrozil (Lopid); fenofibrate (Lifibra, Tricor); clofibrate (Abitrate, Atromid-S); and bezafibrate (Bezalip).