For two solid years, Dr. Perry Molinoff and his colleagues methodically tinkered with a couple of molecules they had identified the old-fashioned way--by testing tens of thousands of compounds on cultures of growing cells. Among other things, they adjusted certain structural features to reduce the chance that the molecules would cause gastric distress and to increase the likelihood that they would cross over the blood-brain barrier. And all the while, they checked and rechecked to make sure that during this biochemical shuffling they did not lose the key property that made these particular molecules potentially so valuable: their ability to block the activity of gamma secretase, an enzyme thought to play a critical role in the development of Alzheimer's disease.
Out of more than 100,000 candidates in the initial screen, says Molinoff, head of neuroscience drug discovery at Bristol-Myers Squibb, only two were deemed promising enough to continue working on. That was in 1996. Now, thanks to the efforts of nearly 40 scientists--some at Bristol-Myers' Wallingford, Conn., research institute, others at SIBIA Neurosciences, based in La Jolla, Calif.--the number of compounds derived from these two templates has expanded to more than a thousand.
Last year one of these highly refined derivatives became the first so-called secretase inhibitor to enter clinical trials with Alzheimer's patients, and others seem sure to follow. In fact, not just Bristol-Myers Squibb but also Amgen, Elan Pharmaceuticals, Eli Lilly, Merck and SmithKline Beecham are racing to develop similar compounds. The reason? Over the past five years, an explosion of insights into the genetics of Alzheimer's has bolstered confidence that gamma secretase and a related enzyme called beta secretase are not innocent bystanders but rather are intimately involved in the disease process.
The rapidity with which this new class of drugs has emerged is nothing short of stunning. Of course, until the clinical trials now under way render a verdict, no one knows whether any of these novel compounds will turn into a pharmaceutical Cinderella, but at least the possibility is there. "Compared with what [Alzheimer's researchers] had coming down the pipeline a couple of years ago, it's night and day," says Dale Schenk, vice president of neurobiology at Elan Pharmaceuticals in South San Francisco. "Finally we have moved out of the laboratory and into the clinic."
Alzheimer's disease, many experts are all but convinced, starts with the abnormal buildup of a protein known as beta amyloid. The chief constituent of the scarlike plaques found in the brain of Alzheimer's patients, beta amyloid is made by nerve cells when beta and gamma secretase execute a one-two snip that cuts a larger precursor protein into a shorter fragment. Sometimes the fragment is 40 units long, sometimes 42. The slightly longer variant, scientists have found, is directly toxic to nerve cells. Among other things, it appears to stimulate the release of oxygen free radicals, thereby setting off in the brain a destructive biochemical cascade.