For the most part, the biologists on a drug discovery project expect us in the med-chem labs to be able to make pretty much anything we need to make. Actually, I don’t have to go that far – the other chemists more or less expect that, too. Chemistry’s a big field, with a lot of reactions and techniques, and if you want some particular structure badly enough, there are usually ways to get to it.
But not always, and not always by routes that you’re willing to put up with. That’s especially true early in a project when you need some robust chemistry to turn out a lot of diverse analogs quickly, so you can have some idea of which parts of the molecule are most important. Synthetic trouble at this stage is frustrating for everyone involved.
I was on a project a few years ago that ran into this exact problem. Compounding the pain was the way the lead compound looked when it was up on a screen during a meeting: small, perfectly reasonable, easy to deal with. Hah! It was a werewolf, that thing. None of the ideas that we had ever worked out the first time, and many of them never worked out the last time, either. Meeting after meeting would take the same format when there were outside managers or other chemists present: “But why don’t you just. . .” “We did. It doesn’t work.” “But then you should try. . .” “We know. We tried that. It doesn’t work.” “Well, OK, but then you could always come around and. . .” “We could. If it worked. But it doesn’t.”
New chemists would be added on to the program to try to get things moving, and they’d always come in rolling up their sleeves, muttering “Do I have to do everything myself around here. . .” How do I know? Because I was one of them. Within a month or two, though, I was in the same shape as everyone else on the project, looking at a bunch of NMRs and mass spec traces and trying to figure out what went wrong. Meanwhile, helpful folks would wander past the whiteboard and ask me how come we hadn’t tried the reaction that had just failed for the eleventh time. Eventually we learned to offer the more persistent questioners a supply of our starting material so they could solve the problem themselves and be heroic, but nothing ever came of that.
The project managed to stagger to a clinical candidate, but ran into mechanistic problems in the more advanced animal models. (That was really the hot fudge topping on the whole sundae – this was one of those therapeutic areas whose definitive animal models were too complex and costly to run until you were absolutely sure you had The Compound). I haven’t run into one quite like this since, and with any luck, I never will.