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Volume 87 Issue 15 | Web Exclusive
Issue Date: April 13, 2009

Cover Stories: Weighing Options

Generation Next

Two examples show how digging deeper into obesity biology can reveal new insights
Department: Science & Technology
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Cannabinoid 1 receptor-targeted drugs are not the first high-profile failure in drug development for metabolic diseases.

For instance, several drugs that act on peroxisome-proliferator-activated receptors (PPARs), which are associated with obesity, stumbled over safety concerns in the 2000s (C&EN, Oct. 20, 2008, page 34). And in the late 1990s, a combination of two drugs, fenfluramine and phentermine, better known as the mega-selling weight-loss combo Fen-Phen, ran into trouble with the Food & Drug Administration when physicians at Mayo Clinic noticed heart valve defects in some people taking the drug. Other studies linked fenfluramine to high blood pressure in arteries that supply the lungs.

Phentermine was not found to be associated with Fen-Phen's cardiovascular side effects. It is still available on its own, but it stops helping patients lose weight after three to six months.

At Arena Pharmaceuticals, researchers are revisiting the target of fenfluramine. Fenfluramine, which was pulled from the market in 1997, is a racemic drug; one of its enantiomers, dexfenfluramine, was marketed as Redux and was also pulled.

Fenfluramine activates receptors that bind 5-hydroxytryptamine (5-HT), also known as serotonin. Activating a subtype of serotonin receptor found in the hypothalamus, called 5-HT2C, is thought to decrease appetite. 5-HT2C is related to receptors called 5-HT2B, which are found on heart valve cells, and 5-HT2A, which are associated with perception, sleep, and blood platelet function.

Arena believes Fen-Phen had adverse effects because fenfluramine wasn't selective for the 5-HT2C receptor, says Brian M. Smith, director of medicinal chemistry at Arena. "Although fenfluramine stimulated the 5-HT2C receptor in the hypothalamus and caused weight loss, it also released serotonin and activated other serotonin receptors, including receptors in the heart" that likely caused the heart valve defects, he says.

Arena's candidate, lorcaserin, was designed to selectively activate 5-HT2C (J. Med. Chem. 2008, 51, 305). Unlike Fen-Phen, which is a combination therapy, Arena is developing lorcaserin to be sold as a monotherapy, Smith says.

Lorcaserin is currently in Phase III clinical trials. In Phase III data reported on March 30, patients on lorcaserin lost more weight over one year than those on placebo. "Arena is looking very carefully at heart valves," and lorcaserin's selectivity does seem to be translating into an absence of heart defects, says Frank Greenway, a physician at Pennington Biomedical Research Center, a hub for obesity research located in Baton Rouge, La. Greenway also works as a consultant for companies developing obesity drugs, such as Orexigen Therapeutics.

Sometimes, safety isn't the challenge. Orlistat (Roche's Xenical), a drug that blocks pancreatic lipase enzyme and prevents fat from being absorbed into the body, is FDA approved for treating obesity, and a low-dose version, marketed as alli, is sold over the counter. Some patients who take orlistat develop socially embarrassing side effects, including flatulence and oily stool. "Side effects emerged in Phase III clinical trials, but it wasn't appreciated how much of a problem they were until the product first went into the wider population," says Roger Hickling, research and development director of Alizyme, a U.K.-based company also working on obesity drugs.

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Alizyme's leading candidate for treating obesity, cetilistat, has the same lipase target as orlistat. But there are important differences in how cetilistat behaves in the body, Hickling says.

"Orlistat molecules are ideally configured for hydrogen-bonding between two molecules," Hickling says. "Our hypothesis is that the nonpolar part of orlistat sits in the membrane of the fat micelle and the polar part sticks out of the micelles and forms dimers, bringing micelles into proximity. We think that orlistat gives you a coalescence of fat micelles leading to what we call a lipid lake," and that this lipid lake is in part to blame for orlistat's side effects, he adds.

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Cetilistat, in contrast, is a bicyclic molecule without the functional groups needed to form dimers, and it therefore shouldn't cause fat micelles to coalesce, Hickling says. The team has done computer modeling to support their hypothesis, but they don't yet have clear experimental evidence. "We'd like to find a biological model that would be testable, but it isn't the easiest hypothesis to replicate outside the human body," he says.

In Phase II clinical trials, cetilistat together with diet changes was effective at promoting weight loss, with very few reports of gastrointestinal side effects. Alizyme has launched Phase III clinical trials of cetilistat in Japan, in partnership with the pharmaceutical company Takeda. Because taking orlistat has been found to stave off type 2 diabetes, Alizyme plans to explore cetilistat's utility in that area as well, Hickling says.

 
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