I also mentioned recently that I’d come across a good example of an academic compound with interesting activity but no chance of being a drug. Try this one out, from Organic Letters. Yes, there aren’t many other compounds that do what this one does (inhibit the production of TNF-alpha). And no, it’s not going to be a drug – well, at least the odds are very, very long against it.
Why so negative? Several reasons. For one thing, this molecule is extremely greasy. This is not a killer in and of itself, but it’s inviting trouble, for the reasons noted here. The second problem is that this thing looks like it’s going to have some trouble dissolving. That’s trouble both from both the thermodynamic (eventual amount in solution) and kinetic (speed of dissolution) senses. That greasiness will be the problem with the former, since a lot of this molecule’s surface area gives water molecules no incentives to join in on anything. And all those aryl rings (along with the symmetric structure) are asking for trouble with the latter. Those features make the structure look like it’ll form a very good, very happy crystal, with its aromatic rings stacked onto each other like ornamental bricks. “Brick” is the very word that comes to mind, actually.
But solubility is only the beginning. The real problem is that catechol functionality in the center of the molecule, which is just waiting to turn into a quinone. In medicinal chemistry, no one wants quinones; no one likes them. They’re just too reactive. It would not surprise me for a minute to learn that this group, though, is the reason for the compound’s activity. It’s probably reacting with some functional group on the surface of the target protein and gumming up the works that way. It’ll do that to others, too, if it gets the chance. There are all sorts of weird little quinones in the literature that hit proteins that nothing else will touch, but none of them are going anywhere.
No, it’s safe to say that any experienced drug-company chemist would draw a red X through this one on sight. Plenty of reasonable-looking compounds turn up with unanticipated problems, so we don’t need to go looking for trouble. That’s not to say that it can’t be a research tool (although I’d be careful interpreting the data from complex systems – there’s no telling how many other things that quinone is going to react with).
But all this brings up another thing that we were talking about around here – how much do drug companies owe academia for working out fundamental biochemistry and molecular biology? What if someone uses this very compound, for example, as a research tool and discovers something about its target that could be used to develop an actual drug? What do we call that?
Well, we call that “science”, as far as I can see. Everything is built on top of something else. In a case like this, the discoverers of this current compound, even if they’ve patented it, do not have a claim on what discoveries might come from it later on. An even stronger case was decided in that direction – the University of Rochester’s discovery of the COX-2 enzyme, the patent for which led to their attempt to claim revenue from Celebrex. The judge ruled, absolutely correctly in my opinion, that the discovery of a drug target is not the discovery of a drug, and that the effort and inventiveness needed for that second step is more than enough for it to stand on its own.
There’s a “research exemption” for patents, giving legal room to use the disclosed inventions and compounds to make further inventions. I think that’s an extremely important concept. It lets academic labs study patented industrial compounds for their own purposes, and it even lets companies do that to each other. How would we compare our internal compounds to the competing ones if we couldn’t use them? (There’s more than one research exemption, though, and the traditional common-law one took a big hit a few years ago in Madey v. Duke, which worries me).
I strongly oppose broad patent claims for uses and pathways, because I think that these cut into legitimate research. Patents should cover things that are novel and useful. They should completely disclose the substance of their invention. And in return for the period of exclusive rights, anyone else who wants to should be able to get to work on what will replace them. A patent is not a license to kick back; it’s a reminder to keep moving.