This article from Science is a good look at the scientific state of organic synthesis in the pharmaceutical industry. It covers a range of topics which will be familiar to regular readers of this blog as well: synthetic advances such as late-stage functionalization, new bond-forming techniques (photoredox chemistry in particular), the intersection of biomolecules with synthetic chemistry (both engineered enzymes as reagents and the use of organic chemistry on other biomolecules in turn), high-throughput experimentation for discovery of both new analogs and new reactions, and others. These are all solid topics and definitely represent where organic synthesis is in drug discovery, and I would particularly recommend the article to academic chemists who’d like to know what’s going on in this side of the business.
Reading through the paper and thinking about the times I’ve written about these topics, though, it occurred to me that not one of them has come up without some grumbling in the comments section here – grumbling, it must be noted, from some chemists in the audience themselves. Photoredox is a prime example – I don’t think I’ve written about it once over the last few years without at least a few orange peels, beer bottles, and half-eaten hot dog buns descending from the stands. Comments get made about “it’s all a bunch of stuff to get into Science and Nature“, or how it’s just an academic toy, or it will never be actually useful, or a sort of general sense that isn’t it awful that people do this stuff instead of real chemistry? Meanwhile, other chemists have been quietly taking it up, and it’s now used all the way up to large scale because it allows for bond formations that you just can’t get anywhere else. That’s going to continue, too, because new reactions just keep getting discovered.
Now, blog comments are hardly representative of an entire field (the great majority of readers here never comment at all). And the ticked-off commenters aren’t even representative of the comments section in general, but they’re always present. My own take is that it’s a longing for How Things Used to Be, and that’s only partly for the chemistry of yore. Everyone has their own idea of when the Old Days were, but in general it apparently was the time when lots of real analogs and real SAR compounds were made with real chemistry. . .by lots of real chemists. And I think that last part is a key. People remember days when chemistry departments were larger, and somehow felt more central to the whole business, and employment in them was easier to obtain and easier to hold on to. That remembered era (whose doom was heralded, in retrospect, with the big Roche layoffs of 1985) gets mixed together with all its other features of the time, down to the kinds of chemistry being done. Later techniques and developments pick up a smell of outsourcing, layoffs, mergers, and job uncertainty just because of when they occurred.
Now for the “centrality” part. I’ve seen a couple of comments about the Science article to the effect that making the case that chemistry is important seemed a bit defensive. The paper’s title, “The Importance of Synthetic Chemistry in the Pharmaceutical Industry” does seem that way, and the first paragraph makes it explicit:
. . .In recent years, many pharmaceutical companies have chosen to reduce their R&D investment in chemistry, viewing synthetic chemistry more as a mature technology and less as a driver of innovation in drug discovery. Contrary to this opinion, we believe that excellence and innovation in synthetic chemistry continues to be critical to success in all phases of drug discovery and development.
Well, it’s a mature technology compared to several areas in biology, and suffers by comparison. I think one of the underlying problems, though, is this argument that I was making in Chemistry World: that synthetic chemistry is rarely, if ever, a rate-determining step in drug discovery. The real killer in this business is the near-ninety-per-cent failure rate in human clinical trials, and that’s down to target selection and to toxicity. Synthetic organic chemistry doesn’t directly attack either of those; they’re tangles of complex biology that we don’t understand well enough to ameliorate yet.
Chemistry has a lot of contributions to make – the Science article is certainly right about that and it does a clear job of laying out the state of the art. But better, cleaner, faster ways to produce totally new types of chemical matter and to quickly home in on active, selective molecules (which is what all these synthetic advances are aiming for) . . .all of that is for naught when you find out that the mechanism of action isn’t actually enough to provide a clinical benefit. Or that it was the wrong target completely. Or that some other pathway that you’d never heard of and never thought to counterscreen against has kicked in and given you show-stopping toxicity out what was a clear blue sky. Projects have died from time to time and cost accountants have eaten them, but not for chemistry.