Improving Niacin Could Treat Cholesterol, Reduce Heart Attacks, Strokes

Newswise — 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 reported today.

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 scheduled for presentation at the 233rd national meeting of the American Chemical Society, being held here this week.

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."

The American Chemical Society — the world's largest scientific society — is a nonprofit organization chartered by the U.S. Congress and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.

The paper on this research, MEDI 224, will be presented at 10:05 a.m., Tuesday, March 27, at McCormick Place Lakeside, Room E353 A/B, Level 3, during the symposium, "Mechanistic Approaches to Increasing High Density Lipoprotein Cholesterol."

Graeme Semple, Ph.D., is Vice President of Discovery Chemistry at Arena Pharmaceuticals, San Diego, Calif.

ALL PAPERS ARE EMBARGOED UNTIL DATE AND TIME OF PRESENTATION, UNLESS OTHERWISE NOTED

The paper on this research, MEDI 224, will be presented at 10:05 AM, Tuesday, 27 March 2007, during the symposium, "Mechanistic Approaches to Increasing High Density Lipoprotein Cholesterol." It is embargoed for 10:00 a.m., Central Time, Tuesday, March 27.

MEDI 224Niacin receptor agonists

Program Selection: Division of Medicinal ChemistryTopic Selection: Mechanistic Approaches to Increasing High Density Lipoprotein CholesterolGraeme Semple, Medicinal Chemistry, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121

Abstract Niacin is a water-soluble vitamin that at high doses in humans, favourably affects essentially all serum lipid and lipoprotein parameters, including HDL. The use of niacin is however, limited by its associated side-effects, including a highly uncomfortable cutaneous flushing. Recent mechanistic investigations have shown that niacin can activate GPCRs localized on adipocytes. The resultant decrease in intracellular cAMP leads to inhibition of lipolysis, via negative modulation of HSL, thereby decreasing plasma free fatty acid levels and ultimately, it is postulated, raising HDL. Two Gi-coupled orphan GPCRs that share 95% identity and which are both expressed in human adipocytes and macrophages have been identified as possible molecular targets for niacin. In this presentation, the discovery of the Niacin receptor GPR109a will be outlined. The identification of multiple series of agonist ligands for GPR109a and GPR109b via both HTS and classical SAR approaches across will be described. The in vitro and in vivo assay systems that enabled us to identify compounds with favourable properties for further investigation will be discussed, along with hypotheses of how the lipid lowering and flushing effects of GPR109a agonists may be pharmacologically separable even though they are both receptor dependent.

Researcher Provided Non-Technical Summary

Briefly explain in lay language what you have done, why it is significant and what are its implications (particularly to the general public)

Niacin is currently the most effective therapeutic agent for increasing levels of HDL-cholesterol, commonly known as the "good" cholesterol due to the strong correlation between higher HDL and a reduced risk of coronary heart disease, and is widely used for the treatment and prevention of atherosclerosis. Although niacin has been prescribed for its HDL raising effects for decades, its use is limited by its associated side-effects, including a highly uncomfortable cutaneous 'flushing' which contributes significantly to poor patient compliance. 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 further reduce the risk of heart attack and stroke.

Recent investigations of niacin's mechanism have shown that niacin can activate two closely related targets. Both targets are G-protein coupled receptors, or GPCRs. These targets, termed GPR109a and GPR109b, are localized primarily on fat and immune cells. We have focused the bulk of our efforts on identifying compounds that activate GPR109a as niacin has significantly higher activity at this receptor than its close relative. The activation of one or both of these receptors by niacin may be responsible for both the positive anti-atherogenic effect and the flushing effect observed with niacin. With these putative molecular targets identified, it has become much more feasible to embark on a discovery program to find niacin-like compounds with profiles that could improve safety, efficacy and patient compliance.

In this presentation, Arena's discovery of the Niacin receptor, GPR109a, will be outlined. Also, the identification of new agonists, or activators, for GPR109a via a high throughput screening approach and a classical structural-activity relationship (SAR) approach that examines the structure of a compound and its relationship to pharmacological activity across multiple series will be described. The in vitro and in vivo assay systems that enabled us to identify compounds with favorable antilipolytic properties for further investigation will also be discussed We will present hypotheses of how the in vivo effects of free fatty acid lowering and flushing, seen in animal models with GPR109a agonists, may be pharmacologically separable even though they are both receptor dependent.

How new is this work and how does it differ from that of others who may be doing similar research?

This work has not been reported previously and has been carried out within the last 3 years. In addition, no other pharmaceutical companies have reported on new compounds for these targets in the open literature, althouygh some patents have appeared. Ar