New discoveries offer promise for cholesterol drugs

Apr 1 2007

New discoveries offer promise for developing drugs that improve on the therapeutic profile of niacin, the inexpensive, time-tested B-vitamin that boosts levels of HDL cholesterol, the good cholesterol with the potential to protect people against heart attacks and stroke, scientists report.

Graeme Semple, Ph.D., Vice President of Discovery Chemistry at Arena Pharmaceuticals, San Diego, Calif., described new insights into developing drugs that raise HDL via the same mechanism as niacin in a report presentated at the 233rd national meeting of the American Chemical Society.

In small doses, niacin is the familiar B-complex vitamin, which helps the body metabolize or breakdown carbohydrates, fats and protein into compounds that the body needs to maintain good health. In the high doses prescribed by a physician, niacin can increase HDL by as much as 35 percent and reduce levels of artery-clogging triglycerides by 50 percent.

Doctors have known since the 1970s that niacin can reduce the risk of heart attacks and strokes, but it has not been prescribed as widely as newer and more costly medications known as statins.

The use of niacin is limited by its side-effects, including a highly uncomfortable skin flushing, which contributes significantly to poor patient compliance," Semple explained. "Since currently marketed cholesterol drugs have a more modest HDL-raising activity than niacin, better tolerated HDL-targeted therapies with improved efficacy could provide additional clinical benefits to patients and potentially reduce the risk of heart attack and stroke."

Semple described research toward that goal, including Arena's discovery of a niacin receptor termed GPR109a. It is among a family of so-called G protein-coupled receptors (GPCRs) that have long been considered among scientists as good targets for the development of new drugs.

Molecules termed ligands from the environment outside cells bind with these receptors, which are located on the cell surface. Ligands activate the GPCRs, signaling biochemical machinery inside the cell to either inhibit or accelerate cellular processes.

Niacin activates GPCRs on fat cells, signaling the cells to stop producing fatty acids in a way believed to raise HDL levels. It also can activate GPR109b, a closely related receptor on immune system cells. Semple believes that activation of one or both of those receptors may be responsible for niacin's beneficial effects, and the undesirable side effects.

Semple said data from the joint Arena-Merck research program reinforces the hypothesis that it may be possible to identify a compound that activates the niacin receptor without causing flushing, thereby separating the beneficial effects on fatty acids from the flushing side effect.

"This work has not been reported previously and has been carried out within the last three years," Semple noted. "In addition, no other pharmaceutical companies have reported on new compounds for these targets in the open literature, although some patents have appeared."