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Defending Drug Synthesis

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.

30 comments on “Defending Drug Synthesis”

  1. Hap says:

    It does seem peculiar, though, that R+D (particularly R) is seen as a cost center, when the larger cost sink is in trials and development, and when a significant part of that is because we don’t know enough – when we’re not doing enough research to understand how best to spend the money we do have. It seems that the people running drug companies (or funding them) don’t know or don’t care about this.

    That opinion would argue more for biology spending then chemistry, because that’s what we know less of, but some measure of self-promotion might be necessary if your leaders don’t seem to understand why they’re paying you. If they don’t care, it doesn’t help (but nothing will, as immunity to data appears to be a severe and often fatal condition…unfortunately for other people).

    1. mallam says:

      Unfortunately, better predictive biology for many unmet disease areas need true breakthroughs despite unknown money and research hours spent in industry and academia (grad students and post-docs). We are impatient to treat the patient (and to have new patents for bigger profits). So we do not wait, can not wait, for models that may take additional decades or more to arrive continuing to want treatments for deadly, difficult cancers, Alzheimer’s, etc. So we move on to human trials, having no other option when waiting is not what today’s patient and company profits demand.

      1. Hap says:

        But drug development is at the point where if you find something that works, no one will be able to afford it, and part of that is the cost of failed trials. You can’t know everything (and sometimes trials are the way of knowing what you didn’t know before), but it doesn’t seem like knowing less is a good idea.

  2. anon says:

    Merck seems to own 25% of chemistry papers published in Science these days…

    1. John Adams says:

      And Merck yet has done more than it’s fair share of eliminating both synthetic chemistry and bioorganic chemistry positions….hmmmmm

      1. NoIdea says:

        The question is: can you really blame them?
        It is a business after all, and let’s say Merck would double their number of employed medicinal chemists do you think they’d make substantially more profit over 10 years?

        1. DrOcto says:

          No, but after 10 years they would have (in theory) twice as many new drugs just entering the market.

          1. Org Lett Reader says:

            I can’t agree with your statement here, for the reason that Derek nicely laid out:

            “…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.”

  3. Wavefunction says:

    I generally agree that chemistry is not the rate-limiting step in drug discovery, but cycle times for synthesis – especially the logistics and increasing cost of outsourcing to China and India – still limit how many hypotheses you can test, so new chemistry that could mitigate these constraints will always be welcome. That being said, the title of the piece does sound a bit defensive and probably reflects the state of employment of synthetic chemists in the last few years.

  4. Anonymous says:

    Paywall. I recognize Terrett from the daze of combichem. Oops. Typo. … the DAYS of combichem. To If Derek highlights a paper In The Pipeline, how about making it open access? Thank you.

    1. ex-London Chemist says:

      Would that be Nick “I invented Viagra” Terrett?

    2. Chrisy says:

      The full paper is available on SciHub.

      Every scientist today needs to know how to use SciHub because your institutional access is as tenuous as your job.

      I have institutional access but still use SciHub because it is simply easier. Plus I like to think that in some small way it sticks it to the publishers, who still believe that $45 is a reasonable charge for a single pdf.

  5. Uncle Al says:

    Chemistry is a giant hole for money and costs of disposal…for what? Unlike any other corporate sector, R&D day-to-day largely fails. “Bloody Hell, try Murray’s reagent.”

    Walk into a working synthetic organic lab. That fries corporate minds. They’re…laborers in rotted clothing, in a spaceship. Here in California, inundated with brown snails, the vac line demo was explosive decompression. A cigarette dipped in liquid oxygen sent the wrong message. Magnetic stirrers were intellectually dangerous.

  6. MoMo says:

    64% of the new drugs in the 2018 FDA approved list were small molecules.
    This isn’t even an argument. If you don’t invest in chemistry and support chemists, especially junior ones, society will suffer, if it hasn’t already.

    MOre MOlecules-Less Talk

    1. KO says:

      “More molecules-less talk” I really like this phrase as a personal mantra

  7. AVS-600 says:

    Thinking about R&D as having a rate-limiting step is tempting but is actually a less useful comparison than it might seem like.
    Probabilities multiply with each other, so the fact that clinical trials are the most likely place for a project to wipe out doesn’t matter as much as it seems like, assuming clinical trials are worth running in general (and if that isn’t true, then we as an industry have a much bigger problem). If better chemistry means the chances of getting a human-viable compound out of a project goes from 50% to 60%, and the chance of succeeding at a clinical trial stays flat at 10%, you’ll still see 1.2 times as many new drugs hit the market (specifically, the overall chance in that scenario for a successful project would go from 5% to 6%).

    1. Derek Lowe says:

      The question then is what effect chemistry has on getting a human-viable compound. . .and given the usual reasons for failure, I have to wonder, once you’ve made it to acceptable PK, through animal tox, etc. (Helping to get through those is a good thing, too, but only the first one seems amenable to chemistry in most projects).

      1. AVS-600 says:

        Definitely an interesting question. It seems like the answer should be significantly less-than-linear but also not zero. If I could magically make 10x times as many compounds in the same amount of time, I wouldn’t expect to see ten times as many NME candidates, but I would expect to see slightly better compounds going into the clinic at a noticeably faster rate (this is another way that the rate-limiting step analogy breaks down though: if chemistry becomes 10x as productive, then assays and PK become bottlenecks, but if chemistry were consistently 10x as productive, an efficient company would try to have more staff doing assays and PK rather than accepting that bottleneck permanently). There’s always a trade-off between finding the best compound and finding a compound that meets deadlines.

        1. azetidine says:

          No it doesn’t. Being a good chemist is akin to keeping a train engine running perfectly well. It doesn’t matter how good you are if the tracks are headed for a cliff.

  8. yep says:

    I’m not really sure the point of this article. It’s a good review of the types of papers Merck has been publishing, but I don’t think it makes the case that these innovations really are game changers for discovering and developing new medicines (or at least we aren’t seeing their accelerating effects yet with new small molecule filings from them driven by this tech). I agree with Derek that it all comes down to understanding the biology and clinical outcomes. The chemistry is never rate determining, although accessing novel chemical space can offer IP advantages and maybe tweek the molecules a bit to optimize its properties

  9. zero says:

    Pseudo-nostalgia as you’ve described is part of a larger sense of loss and a wish for an earlier, better time. (I say pseudo because plenty of people who didn’t live it or didn’t get the good parts themselves still have this ‘golden age’ view of the past.) The effect of this on politics has been catastrophic.

    The reality is that the ‘good old days’ sucked in almost every way for the majority of people compared to today. The one key thing that has definitely gotten worse for the 99% is employment, and you’ve hit solidly on that vein.

    Far better to be forward-looking. Stay on top of new developments, add to your mental toolbox and be prepared to seize the opportunities in your future. Learn *from* the past, not *in* it.

  10. petros says:

    Nick Terrett was also one of the inventors of sildenafil (Viagra)

  11. PostdocMeNow says:

    How many of these perspective articles are we going to have per year? I could google about three of them from the top of my head. You know, these articles written by industry chemists reassuring themselves of their worth.

    Just give me an industry bench job already if upper scientific management have enough free time to reuse the same article over and over again.

    1. DireStraits says:

      Yes, I notice at least one of the authors is promoting their own PhD topic. More investment = more jobs!

  12. The Music Man says:

    An occasional grumbler here. To use a food metaphor, it’s not that we were saying that the hotdogs weren’t tasty or didn’t fill your gullet, but rather that some pretty unsavory ingredients were used when the sausage was made. Photoredox can certainly do many things, some of them useful. No argument there. However, certain in the field (and one Ivy League lab in particular) have not only pushed the concept of “salesmanship” to its absolute breaking point, but also done so without citing ample precedent in the photochemical and radical literature (“I invented the field!!”) and through some unsavory lab practices. Maybe cross-coupling was the same during the Pd bandwagon heyday, or total synthesis during the Taxol race. I wouldn’t be surprised. Still, when the next Harold Hill waltzes into town promising the “next big thing” I think that there’s some value doing a reality check.

    1. Damion Lillord says:

      I cannot wait to read “In the Pipeline” comments years into the future when the people harmed by the “unsavory lab practices” are finally able to speak freely about their stories. In the meantime, it would be a compelling tale for an investigative science journalist interested in (likely) misconduct, exploiting academic hierarchy and gender power imbalances for scientific career gain.

  13. PhotoDeTox says:

    Photoredox is the current hype in synthetic chemistry as we have seen other hypes before (C-H activation, organocatalysis …). However, a few methods will remain and become a standard in our synthesis toolbox. We would be fools not to make us of it – where it makes sense.

  14. Chrispy says:

    The only chemists I know who are still doing chemistry have soured on the industry and are looking to get out. I feel very lucky that I dodged this bullet in Grad school and went into biology instead. It is a sad state of affairs.

  15. Mister B. says:

    Not experienced chemist here (freshly graduated 🙂 ), but to me, synthetic chemistry applies more in dev processes. Where it needs to be more efficient, greener, and so on…

    Maybe this is why I like OPRD journal so much !

  16. eub says:

    Oh, no props for the Edna St. Vincent Millay? Here you are then.

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