From Pisces To Prodrugs: An Obesity Story

Sockeye salmon (Shutterstock)

When it comes to obesity, the drug race between Arena's lorcaserin, Vivus's Qnexa and Orexigen's Contrave is at the forefront of folks' minds these days. But yesterday at the ACS National Meeting in Boston, I sat in on part of a session in the Division of Medicinal Chemistry that gave me a broad overview of other strategies for developing treatments for obesity. I heard a neat story from Donald L. Hertzog of GlaxoSmithKline that I thought I'd share. GSK is focusing on the melanin concentrating hormone receptor protein as a target for obesity drugs. When I read the abstract, I thought I'd made a mistake. What in the world could the pigment melanin have to do with obesity? It turns out there's a fascinating connection. Researchers first found melanin concentrating hormone, a cyclic 19 amino acid peptide, in salmon. As you might expect, it plays a role in pigmentation of fish scales. In humans, however, the hormone doesn't play a role in skin pigmentation. It's made mostly in the human brain, in regions such as the hypothalamus. "When you see something released in the hypothalamus alarm bells should go off- because it could be important in feeding," Hertzog said. That turned out to be the case. Researchers soon found that levels of the hormone go up during fasting in mice. And that mice lacking the receptor for the hormone were not only lean, they were resistant to diet induced obesity. GSK set out to make molecules that block melanin concentrating hormone receptor-1 as potential treatments for obesity. They found a promising molecule in GSK282254, which not only inhibited the receptor but as Hertzog put it, had "a lot of areas to get your hands on" for making analogs. When the GSK team replaced a simpler aromatic ring on GSK282254 with a bicyclic thienopyrimidone ring system, they saw a 15-fold boost in potency for inhibiting the receptor. After several more rounds of optimizing, they discovered GW856464, a compound that eventually made it to human clinical trials for treating obesity. Unfortunately, the molecule didn't reach its site of action efficiently when taken orally. So GSK went back to the drawing board to find a way to improve the drug's properties. They decided to try a prodrug approach-temporarily masking part of the drug candidate with a functional group that the body's own enzymes will remove. Sure enough, when the team tacked the amino acid valine onto a hydroxyl group of GW856464, they made a prodrug with almost 6-fold higher bioavailability. This prodrug was selected for preclinical evaluation as a potential clinical candidate. Plenty of obesity drug strategies exist- it'll be interesting to see which of them succeed. More reading: J. Med. Chem. 2006, 49, 4017. Bioorg. Med. Chem. Lett., 2006, 16, 4723. MEDI 283- abstract from Boston ACS National Meeting (pdf) Salmon image credit: Shutterstock Updated 8/26 - fixed stereochemistry on GW856464

Author: Carmen Drahl

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