Here’s an article in Nature Chemistry on organic synthesis and drug discovery, from a distinguished group of drug-industry chemists. The authors are going over a number of areas where medicinal chemistry could make use of more advanced synthetic techniques, and they’re good ones.
For example, “From an industry perspective, the most common challenge for any new synthetic method is its level of tolerance to the polar functional groups and nitrogen heteroatoms found in biologically active molecules.” Yes indeed. That’s what I look at when I see a neat new transformation in the literature – what did it work on? Basic amines OK? Tertiary or secondary? Secondary amides tolerated? Carboxylic acids? Free OH groups? I’m disappointed sometimes when I find that a reaction can’t tolerate these, but I’m glad that the papers involved at least went to the trouble of finding the limits to their chemistry. Far worse than that is a paper that tiptoes around the issues of chemical compatibility, leaving you to find out for yourself – if you’re so inclined, and often one is not.
Another area identified is late-stage functionalization, C-H bond activation, etc. Those reactions are always welcome, for sure. Chemical diversity is one of the names of the game that we play, and anything that allows us to get more of it quickly and reliably is good news. Blending with the above, the more complex and functionalized the molecules that can be used as substrates for such chemistry, the better. We’ll take fluorination, hydroxylation, amination, addition of methoxy, trifluoromethyl, what have you. It’s great to be able to predict where the functionalization will happen, of course, but there’s value in things that just sort of go in and mess with structures, too: new molecules! After all, that’s what the liver enzymes do to our drugs; we’re used to it.
The paper also calls for new ways to synthesize and functionalize small heterocyclic rings, new metal-catalyzed coupling reactions (and new C-C bond-forming reactions in general), more biomolecule-compatible reactions, and more. It also goes briefly into machine-assisted synthesis and software-assisted retrosynthesis, but the bulk of the paper is on synthetic methods, and I can only cheer on their suggestions. These are all potential areas for academic-industrial collaboration to generate new chemistry, because everyone benefits from success in these areas (indeed, some of this collaboration goes on already for just these reasons).
So I enjoyed this paper very much, but it starts off with a claim that’s worth arguing about: “organic synthesis is still a rate-limiting factor in drug-discovery projects“. Is that true?
It depends on where you’re standing. All the synthetic limitations described above are real, and they keep us from being able to make a lot of molecules that we’d otherwise be cranking out. But (and this is a big point) it’s rarely the case that we medicinal chemists identify a tricky new structure that absolutely has to be made. That sounds odd, but it comes down to our predictive powers, which aren’t so great. We don’t generally draw some wild compound up on the hood sash and say “That’s the one, folks: find a way to make it or die trying”. We never know which is the one, so in the absence of knowing, we make the things that we can make in the ways that we can make them, and honestly, much of the time, we can manage to come up with something.
In a more general sense, though, things like the ability to make more polar compounds reliably and quickly would probably lead to better and more structurally diverse drug candidates and screening compounds, not to mention better starting points for projects in general. We just don’t know which ones. The main examples of specific compounds I can think of are metabolites or potential metabolites, where the liver has made some new polar compound out of an existing drug candidate, and we need to make the new compound(s) for testing. Those can be tough, and sometimes the only way is to grind out small quantities by exposing the drug to liver tissue itself (!)
As for times we can’t come up with something, I would like to believe that far more diverse and interesting sets of compounds, millions of them, would allow for real hits to be found against target classes that we currently have trouble attacking. But that remains to be proven, if it ever can be. Chemical space is so large that you can always say “Well, your compound set still wasn’t big enough – the good ones are still out there”, and there’s no way to say that’s wrong.
Overall, the real killers in drug discovery stem from – to put it mildly – our incomplete understanding of biology. It’s Phase II and Phase III failures that hammer us, and those happen because we don’t understand our desirable (and undesirable) mechanisms of action enough, leading to failures in efficacy and safety. Even worse, they come after a big pile of money has been spent. Compared to these problems, generating chemical matter is not as big a concern. We already generate enough chemical matter to send all sorts of stuff into the clinic, where 80 to 90% of it dies for other reasons entirely.
Organic chemistry is, of course, crucial to making small-molecule drugs, and you’d think that would be enough. But as a chemist, I wish that organic synthesis were more relevant to these deep problems. But in the big picture, it isn’t quite so. Chemical biology, as a field, is an attempt to make that happen, but How to Make will never be able to answer questions of What to Make and Why.