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Cardiovascular Disease

The Beginning? It’s Right Past the End. . .

There’s a paper in the latest issue of Science from a team at Schering-Plough that may have tracked down how the company’s cholesterol absorption inhibitor (Zetia, ezetimibe) works. That news really takes me back.


It’s been years now, so it won’t do any harm to mention that I used to work there. I had a ringside seat for the early years of that project, because it all happened right around the corner from my old lab. Ezetimibe was discovered fortuitously when one of my colleagues synthesized and sent in the original structures of the class for a project targeting a cholesterol handling enzyme known as ACAT. I believe that the in vitro assay was down that week, so the compounds went into the open slots for mouse testing, where they worked better than anything they’d seen. But when the protein assay came back on line, it was discovered that the compounds had no affinity for ACAT at all. Food for thought, that was.


The chemist involved was named Duane Burnett, and a search for “Burnett DA” in Pubmed will send you to most of the chemistry literature on the subject (along with this review). He had indeed hit on some features of a cholesterol binding site (which was his aim, based on blackboard-level structure modeling – no computers involved.) The compounds seemed to hit an unknown target in the small intestine that helped transport dietary cholesterol. The search for the protein involved began in about 1993, and seems to have concluded successfully in 2002-2003, years later than anyone thought it would take.


In the mid-1990s, all the classic methods for tracking down an unknown binding site were tried. The lead structure was biotinylated, modified with radiolabels, photoaffinity tags, and fluorescent groups (along with various combinations of these.) None of these methods identified the target.


They finally tracked down the protein by brute force genomics, using a cDNA library prepared from rat intestinal lining, coupled with sequence searching for the features you’d expect in a transmembrane protein with a steroid binding site. The evidence seems clear that the protein they’ve found is a key for ezetimibe’s actions, but – most oddly – it still doesn’t seem to bind to the protein. That would certainly explain the failure of all those modified compounds to pull out the target, but it does make you wonder what’s going on. (Is there another real target? But if so, why wasn’t that identified through the modified compounds? And so on.)


It took a lot of nerve to go on with that project, and I have to salute the people who kept it going. As with many other successful projects, there were several points along the way where it seemed like the whole effort was going to fail. As it turns out, ezetimibe is one of the main (few?) bright spots in Schering-Plough’s portfolio. Merck, their eventual partner for the drug, values it pretty highly, too. I’m glad I got the chance to see it happen.


Credit where it’s due! I should note that ezetimibe itself was synthesized by another former colleague of mine, Stuart Rosenblum. He and a host of others developed a huge series of analogs, which built in more acitivity and greater in vivo stability. Just the way drug development is supposed to work, actually.