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New Drugs and New Structures

Here’s an interesting paper that’s just appeared in ACS Med. Chem. Letters. The authors (Todd Wills and Alan Lipkus, both working at Chemical Abstracts) have gone back over drug approvals with an eye to the chemical structures involved (and working at CA certainly gives a person a leg up on doing that!) They’re addressing the broader topic of pharmaceutical innovation by asking how often new drugs also have new structures that have not previously appeared in any approved medication. Update: here are more thoughts from Wills on this at his own site.

This is done at two levels of detail: scaffold and shape. The former is what you get after you prune all the acyclic side chains off of a structure, and the latter is that scaffold after you set all the remaining atoms back to being just plain carbons. Most approved drugs have some sort of ring in them, so you don’t lose too many by these techniques, and the authors identified the set of 1,089 New Molecular Entities (NMEs) that have been approved by the FDA since 1938. And they assigned the structures of these compounds into one of three classes: “Pioneers” are compounds whose shape and scaffold had never been used in an NME before. “Settlers” are those whose general shape had been used, but not the particular scaffold (so it would allow for moving nitrogens around and the like). And “Colonists” are compounds whose shape and scaffold had already been used, and thus differ only in the side chains.

It turns out that Pioneer molecules are in fact over-represented in lists of therapeutically innovative molecules, which is good to know for sure. As a synthetic chemist, that’s what you would like to hear, but it’s good to see it quantified. And Pioneers are followed (eventually) around 20% of the time by roughly similar Settler molecules, and Settler molecules are eventually followed about 20% of the time by similar Colonist ones. Students of med-chem history may be reminded of Sir James Black’s line about how the best way to find a new drug is to start with an old drug! And indeed, Colonist-class drug structures were the most numerous of the three in FDA approvals from about 1970 to the early 2000s, but since then, Pioneer type structures have taken off and established an unprecedented lead. It appears that this is due to two simultaneous factors – the number of Pioneer structures has increased (and has been increasing, in a rough and now accelerating way, ever since sometime in the 1990s), while the number of Colonist structures has been dropping noticeably. (The intermediate category of Settler compounds has been banging along in third place at roughly similar levels the whole time, in case you were wondering).

The last 20 years have seen 248 Pioneer structures approved, and the authors take a closer look at these. In the 2000-2004 period, Big Pharma companies (AbbVie, AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly, GSK, J&J, Merck, Novartis, Pfizer, Roche, and Sanofi) accounted for 43% of the Pioneer structure drugs approved, but that number has gone down in every subsequent five-year period, and is now at 30%. But that’s not because the Big Pharma numbers are declining per se; it’s more that the ones coming from everywhere outside that set have increased so strongly. The authors speculate that size and scale of an R&D organization might not be as much of an advantage as it used to be when it comes to having the the resources to make really new structures.

That may well be the case, so it’s interesting to speculate about why that is. Perhaps a wider commercial selection of interesting (and previously-not-used-in-drugs) building blocks? You also wonder about the impact of easy-to-run chemical reactions (metal-catalyzed couplings and so on). Those would seem to be best at generating Settlers and Colonists, but it could be that they allow for easier investigation of novel scaffolds as well. But as for where those new scaffolds come from in the first place, commercial supply is the main change I can think of over the last 20 years. Any other theories?

38 comments on “New Drugs and New Structures”

  1. Nat says:

    Okay, fine, I’ll say it: I probably would have chosen less historically loaded terms.

    These findings do seem like an elegant, if partial, rebuttal to the frequent claim that pharma companies like copycat drugs and minor variations on a theme because they’re lazy and greedy. Or am I reading too much into it?

    1. albegadeep says:

      Having been prescribed Nexium, then having my insurance deny it, then finding out it’s just omeprazole (a generic!) but filtered to just the S-enantiomer at 50x the price, I do suspect that sometimes copycatting/evergreening due to greed does sometimes happen.

      1. Patrick says:

        I think it happens basically every time companies think it’s practical. Why wouldn’t it?

        They absolutely do that stuff. That’s not the same as saying that’s the primary … anything … at most pharma companies.

        “Pharma squeezes every last drop out of existing drugs and close variants whenever they can” and “pharma invests huge amounts in new medicines at basically all times” sound like opposed statements, but I don’t think they actually are.

        1. Marko says:

          It’s true that you can’t fault the drug companies for doing what they can get away with , but you can blame the FDA and the US patent office for facilitating scams like Nexium. There’s nothing novel about resolving a racemic mixture down to a single isomer , when you – and everyone else-knew from day one that one isomer was responsible for the activity. If you want to market that as a new drug , fine , but it should not receive what is essentially a patent extension on the original drug , allowing avoidance of generic competition. It’s not the first time this scam has been used , nor will it be the last , unless the regulators put a stop to it. Given the extensive regulatory capture , I wouldn’t hold my breath on that.

          1. Nat says:

            I thought the patent on the enantiomeric form didn’t prevent generics of the off-patent racemic mix. Am I mistaken? (To be clear, my assumption was that they would make money on the enantiomer because doctors and insurance companies are easily duped, not because they blocked the generic.)

          2. Marko says:

            I wasn’t clear , what I meant was that they avoid generic competition marketing the enantiomeric drug. Yes , eventually they see some competition from the racemic generics , but by then they’ve established a new brand-name dominance , for no good reason.

          3. Marko says:

            And , of course , the generics should be able to make and market the enantiomeric form as well , after standard reviews of chemical equivalence.

            The rule should be that you discriminate the differences between the enantiomeric forms up front. If one form has the desired activity and another form has off-target activity and the adverse effects , you should want to resolve those issues at the outset , not after your racemic mix has entered and saturated the market for a decade or more.

          4. KazooChemist says:

            Can’t reply to a reply without some sort of special login account. Replying to Marco’s 7:10 post. So you believe that anyone trying to get approval for a racemic drug must have a method to resolve the enantiomers and then go through the full blown path-tox, and clinical trials UP FRONT with both of them? That might be ideal, but perhaps should not prevent an otherwise beneficial drug from approval. Given time, experience, and advances In technology it might be shown that one enantionmer is the sweet spot. Shouldn’t those who do the latter work be able to benefit from a patent of their discovery?

          5. Nat says:

            I guess I still don’t have any objection to enantiomer patents, as long as the generic racemic is available. It’s hardly a secret that Big Pharma makes a lot of money selling us drugs we don’t need, but – as long as their marketing is technically FDA-legal – the solution to this isn’t to fire the regulators, it’s more informed consumers. (Outlawing direct-to-consumer advertising might be a part of this, but I am not informed enough to comment further.)

          6. Marko says:

            “So you believe that anyone trying to get approval for a racemic drug must have a method to resolve the enantiomers and then go through the full blown path-tox, and clinical trials UP FRONT with both of them? ”

            No , I think they must either do that or forego any future claims on the individual enantiomers. As long as someone else can come in and do what they didn’t want to bother with , and that party can profit from that effort , I have no problem. That’s not the way it works currently.

            “Given time, experience, and advances In technology it might be shown that one enantionmer is the sweet spot. Shouldn’t those who do the latter work be able to benefit from a patent of their discovery?”

            Yes , exactly , but patent rights don’t work that way today. Those who do the latter work are invariably the holders of the original patent. Broad claims are present in the patents granted for the original compound covering enantiomers , derivatives , adducts with the kitchen sink , etc. Competitors couldn’t touch it without an expensive and lengthy legal battle , which they’d likely lose in the current environment in any case. There’s simply no incentive for others to pursue an almost certain and easy improvement of the original drug , and there’s every incentive for the original patent holder to wait to do so , and double-dip.

          7. Some idiot says:

            Marko, the real-world side of things is a lot more complex…

            For one thing, it is very unlikely that further “enantiomer change” preparations/patents will be coming up in the future, but for that one needs to understand the background to it… Decades ago, chiral separation could actually be quite difficult; even simply doing chiral analysis was often either difficult or impossible. And let alone chiral separations on scale… Additionally, the technologies/methodologies for chiral synthesis were not nearly at the same level as they are now (and particularly not for scale up). And it is decades ago we have to think about it, simply because _that_ is when the R&D was done for the racemic drugs which are currently on the market. Racemic mixtures were then accepted by authorities (eg FDA/EMA) simply because (a) they were considered to be good drugs, and (b) it was accepted that single enantiomers were not a practical option. These days, since technologies and methodologies have expanded in an amazing way, if you tried to submit a racemic mixture to the authorities, you would be laughed away. Simply because we live in another time. Remember, classical resolution doesn’t always work, and even when it “will”, you still have to actually create the crystal form which will do the work for you. And we still do not know what that will be ahead of time! Remember, you can do a salt screening and get nothing out of it, but try again at a later time and be successful… Simply because crystallisation (although thermodynamic) is steered by kinetics. And if you don’t have a scaffold for the crystal, it can take a long, long time for one to just “appear”…!

            Therefore, when the technologies began to appear that could create pure enantiomers of previously racemic drugs, it was natural for companies to examine them. It should be noted that sometimes it gave a better product, sometimes it gave a worse product, and sometimes it made no difference. There are some interesting examples of these in the literature! But it is also relevant to mention that it was not just the original producer that examined these pure enantiomers. Some companies made a business case out of separating enantiomers and patenting them, sometimes selling the pure enantiomer themselves, and sometimes licensing this to the original producer.

            From a patent point of view, again, decades ago it could be difficult or (in a practical sense) impossible to produce pure enantiomers, and therefore the production of pure enantiomers (and their use) could often pass the “inventive and novel” test in order to be patentable. These days, unless something was quite extraordinary, a patent examiner would not allow a claim for a pure enantiomer when the racemate is known, simply because it would not be considered to be inventive or novel.

            I should note that a similar situation exists for polymorphs. Many years ago it was pretty easy to get a patent on a new polymorph, simply because they (the concept) were novel. These days (generally speaking) you need to have an application for a polymorph (eg for use in purification, or better dissolution profile) in order to have a decent chance of getting a patent on it (something similar can be said for new salts; essentially the same deal). Again, over the last few decades the bar has been raised significantly as regards what is novel or inventive (as indeed it should).

            It may be such that “standard” (I know; “standard” is typically only easy for the person who doesn’t have to do it themselves…! 😉 ) formulations (eg normal, sustained release, etc) will be harder to get additional patents on in the future, for more or less the same reason. Unless it can be clearly shown that it gives a benefit. Which, in the end, is what the patent system should be about: trying to push the bar for innovation higher all the time. And yes, there are so many ways that the current system is flawed, but its a hell of a lot better than many other systems…

          8. Willie Gluck says:

            FDA does NOT give 5 year exclusively to an enantiomer when a racemate has been approved. So don’t blame FDA.

      2. emba says:

        This happened to a friend as IIRC nexium has a better dosing schedule.

      3. An Old Chemist says:

        US patent office allows the patenting of new polymorphs also. Many times, pharma companies extend their existing market dominance simply by patenting a new polymorph. When Zantac was the topmost selling drug of the world, a Canadian company tried to patent a new polymorph but Glaxo proved that the two known polymorphs exchange in body and thus warded off the competition.

  2. Barry says:

    It’s interesting to take a binding-blind look at structure. But we remember that the key pharmacophore for e.g. NSAIDs is the (acyclic) acetic acid moiety, and it is the appended rings (and the optional methyl, making a proprionate out of acetate) that colonized the space.

    1. Barry says:

      HMGCoA reductase inhibitors (“statins”) also the key pharmacophore is the acyclic beta-delta-dihydroxycarboxylate chain (which may or may not present as a lactone)
      Focusing on the lipophilic blob of aromatics is to miss the whole point of these drugs.

    2. Derek Freyberg says:

      “But we remember that the key pharmacophore for e.g. NSAIDs is the (acyclic) acetic acid moiety, … ”
      I don’t think that’s the case. If you look at the prototype NSAID, it’s aspirin, which is in effect a phenylformic acid; then there are phenylacetic acids, like diclofenac; then the phenylproprionic acids like ibuprofen. It’s arylacetic acids, etc. that are NSAIDs, not the acetic acid moiety itself: no aryl, no NSAID, generally speaking.

      1. Barry says:

        Yes, the typical NSAIDs require a lipophilic blob. But details of that aromatic teach us little about the drug. It’s the acetic (or proprionic) acid that’s key. Likewise with the HMGCoA reductase inhibitors (statins). The arene can dominate tissue distribution (and can evade a patent), but it doesn’t make the drug.

  3. AVS-600 says:

    How much of the drop in share is from artifacts based on the share of “Big Pharma” companies on their selected list? Is there an effect from companies that simply were too new to the scene in 1995 to have a big impact, but would be considered Big Pharma based on operations in 2020? (Gilead and Vertex come to mind as good examples off the top of my head).

  4. Mo says:

    Is this recent shift towards pioneers because of better science or better ip lawyers?

    1. MTK says:

      Does it matter?

      If the shift toward novel chemical motifs is driven by IP considerations and freedom to operate is that somehow worse?

      The patent system has and remains a great driver of innovation, both for the inventor and would-be competitors. There’s a reason why the Founding Fathers specifically included it in the Constitution, to “promote the Progress of Science and the useful Arts”.

      1. Some idiot says:

        Hmmm… Didn’t know that! Thanks! 🙂

      2. Founding mother says:

        Right… the founding fathers had a crystal ball…. understood crystallography and formulations…. and envisioned the internet and the iPhone…
        Too bad they didn’t see the Don coming!

  5. CMCguy says:

    I propose maybe combichem craze of the 90s probably played a part of the reason for uptick toward more novel molecules. Although it failed in hyped revolution for enhanced drug discovery combichem did alter certain thinking and provided a tool to expand how and where to seek out new structures for biological interactions.

  6. NHR_GUY says:

    What I find interesting is that Pioneers are not a leading indicator of settlers. As a (former) med-chemist, I and many others would look at the shape of a competitor molecule and then try and recapitulate it on another scaffold. It’s med-chem 101 (or maybe 102). You would think this practice would show up in the numbers.

  7. Orange says:

    How much are analytical techniques a factor? New (and presumably more complex) structures are easier to develop if the day-to-day work is simpler with routine access to walkup LC/MS, 2D-NMR, HRMS etc.

  8. Kazoochemist says:

    Replying to Nat (again can’t seem to direct my response to the proper place on this website) .

    You claim to have no objection to enantiomer specific patents as long as the racemic is available in the marketplace. What if the enantiomer specific patent shows harm from the undesired enantiomer? You state that Big Pharma makes a lot of money selling us drugs we don’t need (with no evidence). Would you prevent enantiomer specific patents that seek to prevent patients from taking a now proven toxic enantiomer? Should the entity that makes that distinction not be able to benefit from their research that established the enantiomeric difference?

    1. Nat says:

      There was an implicit assumption in my comments that I should have made clearer, which is that the racemic drug had already been FDA-approved for the same condition as the new pure enantiomer version. This is certainly true for the example above (Nexium/Prilosec) and also Celexa/Lexapro. I do not know the details of how the FDA removes approval for an existing drug, but I assume there is a standard science-based process for this that is independent of the patent office. If a pharma company discovers that its racemic drug is toxic, it should of course notify the FDA immediately and pull the drug from the market, not bury this information in a patent application!

  9. Stanislav Radl says:

    Usually, the most successfull drug is not the first drug of the group on the market. Some me too drug launched later can have better efficiency and consequently also higher sales.

    1. Some idiot says:

      Hence the quote:
      “The early bird catches the worm, but it is the second mouse that gets the cheese…”

      Another effect is that if it is something of a new area, then the first company uses a lot of time and resources demonstrating the usefulness of the effect. Therefore, if someone else comes with better efficacy, they can get into a “pre-made” market…

  10. Adrian G. R. says:

    What about better availability of instruments for use in high-throughput screening and the like? I would imagine this was more reserved for large companies in the past, while it is becoming quite standard in even relatively small labs these days?

  11. Wavefunction says:

    Do the new pioneer structures include macrocycles and other beyond rule of 5 compounds? Those have certainly taken off after 2000.

    1. Derek Lowe says:

      You’d definitely have to think so, yeah. . .

  12. In pain says:

    Did you see the new commercial on TV on “the future of pain”: ibuprofen +aspirin.

    Gmafb

  13. Bill says:

    Heard a new savior buzzword — ICAM.

    Expect I’ll get the 411 here.

  14. Erik Dienemann says:

    The article and comments were a great read. Took me back to my early days in API process R&D at Merck working with some of the best synthetic chemists around and being amazed at how they were able to put molecules together. As a chemical engineer, I’m conversant with organic chemistry but I don’t “get it” like many of you do – I used to joke that it’s all just stick figures to me.

  15. In-the-dark says:

    Naive question: what’s the relationship between these measures of structural similarity of the compounds and mechanism of action of the drugs? In other words, should we expect that that “setters” and “colonists” do the same things (treat the same conditions, the same ways) as the “pioneers” they are following?

    1. Some idiot says:

      Good question, and the short answer is “it is complex”…

      Just to give an idea (and this is a simple case), consider some of the simple neurotransmitters, eg dopamine, serotonin, GABA (and yes, there are many others).

      Each of these neurotransmitters has quite a number of different receptors (dopamine has at least five, and I have lost count of how many serotonin has; north of 15, at any rate). Each of these receptors does something different, so if you activate (or deactivate) one of them (and not as much the others), then you will see an effect (whether or not it is something you want is debatable). Now, all the receptors have different structures, so modifying (say) dopamine will give you a compound that has changed activities at the different receptors.

      So although you start with the same template, you can quickly make compounds which have a multitude of different effects. So… It is complex…

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