As I’ve mentioned here before, publication in the scientific journals is not necessarily a big priority in the drug industry. Patent filings, on the other hand, are very serious business indeed. If you’re an organic chemist looking to see if some particular compounds have been made, you ignore the patent literature at your peril. That’s where most of our med-chem procedures and analogs end up, and there’s a lot of good chemistry in there that never sees the light of day otherwise. Most of it’s even reproducible! (And that’s a crack that you can make about a number of open-literature journals, too, for that matter).
But we do write up papers from time to time. The problem is, it’s often only after the project has been finished for a while. Sometimes it takes that long to decide that the work is safe to publish, and sometimes there are just too many other (more important) things going on. But the result is the same, and I’ve experienced it myself: you go back to the old project data, ready to assemble it into a manuscript. . .and large sections of it appear to make no sense at all.
It’s disconcerting. By “no sense”, I mean that while the chemistry is fine, and the compounds are what they’re supposed to be, it’s nonetheless hard to see why some of them got made in the first place. Whose idea was it to react that amine with every single isocyanate on the whole shelf? None of the resulting ureas were all that good, so why did we decided we needed seventy-nine of them? And there are always gaps in the story that weren’t so apparent while things were going full speed: how come we never made any more of those N-alkyl compounds? And didn’t we resolve that series of racemates at some point? Somebody was supposed to do that.
All this makes it hard to turn many med-chem projects into coherent stories, and a coherent story is what you'd like for a journal publication. Ideally, you want a narrative, something along the lines of: ”We started with this screening hit – promising, but lacking so many key things. By careful, thorough experimentation, we solved those problems one after the other. Moving from strength to strength, and hardly wandering down any blind alleys at all, the analogs became more potent, more selective, and their physical properties and PK fell right into line. In the end, we prepared the wonderful clinical candidate shown in the last table of data on the last page. Not too obvious, is it? Bet you wouldn’t have gotten there yourself. But that’s how good we are.”
Right. The problem is, no projects ever work like that. Or if they do, I've somehow missed seeing them over the last nineteen years. A more realistic story would go something like: “We started out with this screening hit, and decided that we’d change the right-hand side of it – well, the left-hand side, for those guys down the hall who always drew the thing upside down and drove the rest of us crazy. That’s the part of the molecule that had the easiest chemistry, naturally. And naturally, everything we did to it over there made things worse. So the weeks went by, with management tapping their feet, and finally some of the guys said the heck with it and started changing the back end of the molecule. You thought those other compounds were less potent? You should see these! But one of the changes actually worked, for some reason. Then when we went back and starting messing with the easy side of the molecule, two things happened: for one, the chemistry wasn’t so easy any more. But now those changes actually made things better. So we cranked out a whole pile of these things, hoping for the best, and finally got down to two compounds: one with great potency and selectivity, but iffy blood levels, and one with great PK, but not so great on the potency. Never could bridge the gap. We put ‘em both into two-week tox, and they both flunked out for the same completely unexpected reason. They're not gonna be drugs, we've filed the patents already. . .so, here they are!”
Well, you can’t quite say that, not even in Bioorganic and Medicinal Chemistry Letters. So you put things into the most coherent shape you can, and trust your fellow medicinal chemists – those of them who might actually read your paper – to understand. They generally do.