It's been quite a ride, at least for the drug companies fortunate enough to have discovered one. The blockbuster drugs are the ones that transform companies with a flood of revenue, changing them forever in just a few short years while the patent is in force. There's a list of famous names in this category, going back to Valium from Hoffman LaRoche, through Zantac with Glaxo, and leading to the biggest of them all (so far): Lipitor (Warner-Lambert and then Pfizer).
Companies have set up their entire research structures to increase their chances of finding drugs like these. But the time for them may be ending. Many researchers (and you can count me in this group) worry that the "low-hanging fruit" has been picked by now. Drugs (and drug targets) like the ACE inhibitors for high blood pressure or the statins for cholesterol are very thin on the ground. Those were wonderful opportunities: clear biochemical choke points, right in the middle of disease processes that affected millions upon millions of potential patients, with chemical matter that could be found, assayed, and perfected. Those, I have to say, were definitely the days.
But now that we've run through all of these kinds of targets that we know about, we're left with a much harder list. (The genomics frenzy in the industry about ten years ago was set off by the thought that there might be some lay-up targets out there that no one knew about yet). There are still plenty of diseases, of course, whose successful treatment would lead to a blockbuster drug - Alzheimer's is a good example. A general cancer therapy would be an incredible discovery. A safe drug that raises HDL cholesterol (instead of just lowering LDL) would be a winner. And everyone knows that an obesity therapy that really worked would be a massive success, too. But the problem is, we don't know how to find these things, and there's significant doubt about whether some of them can even exist.