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The First Deuterated Drug Arrives

The first deuterated drug has finally been approved by the FDA. It’s Austedo (deutetrabenazine), from Teva, and it targets Huntington’s chorea. This is an interesting development on several levels. The idea of adding deuteriums (instead of plain hydrogens) to drug structures had been kicking around for many years, but only in the last 8 or 10 years has serious development been underway on them.

Some readers outside the field may be wondering what the big deal is, so here’s a bit of background. Deuterium is the (fairly well known) “heavy hydrogen” isotope of regular hydrogen, which is heavy because it has another neutron in it. That basically doubles its weight (the single electron in the atom is a roundoff error in that regard), so these two are an isotope pair with a large percentage difference in weight indeed. (Hydrogen to tritium, the two-neutron isotope, is the single biggest weight percentage change, but tritium is radioactive and is thus out of the running for the use we’re discussing). The reason this weight difference makes a difference is when a bond breaks between the hydrogen (or deuterium) and another atom. The bond is actually harder to break with the heavier isotope, an effect that can be modeled surprisingly well with springs and fishing weights. This is the “primary kinetic isotope effect”, and if that bond-breaking is an important step in some process, you can slow the whole works down by just putting in a D where an H used to be. For drugs, the key is that many of them are metabolized and destroyed when they hit they liver, and this is often done through breaking a C-H bond. So a well placed deuterium (or two, or three) can actually have a significant effect on how long a drug will circulate in the bloodstream, by slowing down the liver’s clearance mechanism.

So Teva’s drug is a version of tetrabenazine, an older compound which has been used for several years as a treatment for movement disorders. The structure has two methoxy groups on its aryl ring, and that’s where one set of metabolizing enzymes hit – as is so often the case, the methoxys are demethylated to the phenol/catechol. Such structures are almost invariably cleared out with dispatch, generally through attaching some other group (like a glucuronic acid) on the phenolic OH, which is pretty much like slapping a red disposal tag on a molecule as far as the kidneys are concerned. Deutatetrabenazine switches both from OCH3 to OCD3, and that’s enough to slow the compound’s clearance down to a useful degree. Actually, both the plain and the deuterated forms of tetrabenazine first get metabolized through reduction of the carbonyl group. That gives you two isomers, only one of which is active, and these are the ones whose methoxy groups get chewed off – it’s the prolongation of the active metabolite’s lifetime that really gives the deuterated form a dosing advantage. Importantly, slowing down that step also give a lot less variability in blood levels, patient-to-patient.

At the site of action, the transporter VMAT-2, both drugs would appear to be basically identical, which is what you’d expect (tetrabenazine is not hugely effective, but it does help). Deuterium is the same size as hydrogen and has the same polarity (or lack of it); it’s just the weight that’s different, and that shows up only when a bond to it is being broken or formed. (Update: see the comments for testimony from analytical chemists that deuterated compounds can act a bit differently, though). That’s the reason that so many people have been looking at deuteration, actually. There’s an excellent chance that if you pick your cases carefully, that you will have a drug that does exactly what a nondeuterated form does, but just lasts longer. This does not always work – nothing always works – because a leader in this area (Concert Pharmaceuticals) had their lead deuterated drug (CTP-499) wipe out in clinical trials a couple of years ago.

In this instance, all that metabolic processing actually slowed down the drug’s path to the market, since last summer Teva was asked by the FDA for more data on the levels of the various metabolites. That didn’t need a new trial, fortunately – the samples and data were still there to be rooted through from the earlier work – but it did slow things down by nine months or so. There are several other deuterated drugs in various pipelines, and the idea itself is now so common that there are likely to be a small but steady number of them hitting the market in years to come.

96 comments on “The First Deuterated Drug Arrives”

  1. biotechtoreador says:

    Wow, so deuterium slows down reactions…..that sounds pretty novel…..I wonder how long until the patents covering this are challenged for obviousness?

    1. Anon says:

      That’s a good point. I was always told all isotopic forms of a drug molecule were covered under the doctrine of equivalence?

      Shouldn’t that mean that the origonal (expired) patent would cover the structure and any generic can make it?

      1. RM says:

        I’m no patent lawyer, but I think what allows deutetrabenazine to possibly get around the doctrine of equivalents is that the difference in metabolism means it *isn’t* equivalent to the non-deuterated form. From what I understand, for US patents the doctrine of equivalents requires that it 1) performs substantially the same function 2) in substantially the same way 3) to yield substantially the same result. Which means you can’t just slap on some 13Cs and 15Ns and claim it’s a non-covered compound. But if you can demonstrate that the function/mechanism/result of the compound is different from the un-isotopic form, I think you have an argument you can forward to the patent examiners.

        1. Anon says:

          “I’m no patent lawyer, but I think what allows deutetrabenazine to possibly get around the doctrine of equivalents is that the difference in metabolism means it *isn’t* equivalent to the non-deuterated form.”

          Good point, but isn’t all of this obvious to one ‘skilled in the art?’

          1. Roger Moore says:

            No. The general principle is well known, but that’s not enough, any more than knowing the laws of mechanics makes all mechanical engineering problems obvious to one knowledgeable about physics. Figuring out which hydrogen can be substituted with deuterium in a way that affects the drug’s half life but not its useful drug properties is far from obvious, even to someone skilled in the area.

  2. DeuteriumAllTheWay says:

    In Deuterium, we trust. All drugs should now have a D in it!

    1. confused says:

      wtf is this comment even about?

      1. Ir(DTF)bpy says:

        You sound like you could use a little D

    2. The D-nald, Med Chemist in Chief says:

      let’s make pharmaceuticals great again: We are going to make only the most deuterated drugs, drugs so deuterated your liver wouldn’t believe it’s possible for a drug to be so deuterated. Your liver is going to get so tired of metabolizing, it’s going to say “Stop, stop, I can’t take it anymore” because of all the deuteriums.

  3. A Nonny Mouse says:

    A slight disagreement here; I once made a CD3 derivative for MS metabolism studies,

    The molecule, an acetyl hydroxamic acid, was being glucuronidated on the hydroxyl. This was 3 positions away from the CH3/CD3 group (CD3-CH-N-OH) and yet the rate of glucoronidation was slowed by about 50%. It is possible, then that 3 deuteriums may have a size effect.

    1. John Campbell says:

      It doesn’t seem to be a size thing but it’s still controversial between electronic or vibrational effects. Bit over my head.
      http://pubs.rsc.org/en/content/articlepdf/2014/nj/c4nj00221k
      http://pubs.rsc.org/en/content/articlelanding/1963/jr/jr9630000866#!divCitation

    2. LiqC says:

      Do you attributive this to deuterium? This would be really odd.

      You have an observation. It needs a plausible explanation and dose dependence (CD2H, CDH2) to say “deuterium causes this”.

      I trust that the studies of CD3 vs CH3 were well-controlled, but I’d be curious to know more details

      1. A Nonny Mouse says:

        It was a long time ago- a mixture of the CH3 and CD3 compounds were given to the animals and the metabolites observed. All that I can remember of the experiment, except for the fact that the CD3 compound persisted over the CH3 and was told it was about 50% difference in rate.

        1. Istvan Ujvary says:

          Though a residual and not biochemical study, DDT and the longer lasting deuterated DDT is an example from the 1960s:
          http://www.biodiversitylibrary.org/content/part/JAMCA/MN_V26_N1_P078-079.pdf

  4. mzspectrum says:

    Binding/affinity changes can be seen with D as well. Even in non-biological case of analytical separation of deuterated analogs on LC-MS. D vs 13C or 15N can alter retention time. Glad to see stable isotopes making appearances in clinics other than as imaging/clinical chemistry applications.

    1. Redlich_Kwong says:

      Agreed. I’ve seen shifts in retention too, but only when a substantial number of deuterium is present.

    2. Isidore says:

      Remember the ICAT (Isotope Coded Affinity Tag) label (still available from Sigma), which is a biotin attached via a linker to an iodoacetamide that can be used to modify cysteines or proteins? The linker, consisting of carbon hydrogen and oxygen, was initially labeled with deuterium (eight or nine non-exchangeable deuteriums, if memory serves). Cysteine-containing peptides could be modified with either the heavy (deuterated) or light (non deuterated) labels, but they could still be separated on RP-HPLC columns. Replacing deuterium labeling with C-13 labeling (eight C-13 carbons, I think) made the retention time difference imperceptible, so heavy and light peptides would essentially coelute. So deuterium labeling did make a difference in hydrophobicity, presumably.

      1. Ted says:

        Indeed I do! I spent about a year trying to advance that technology into class specific warheads (e.g. kinases, phosphatases, etc…). Interesting stuff, we were basically scouring the literature for early stage med. chem. failures (non-selective, covalent binders) to replace the iodoacetamide. In the original work, however, either the deuterium or the 13C versions were expected to co-elute. You could then use the ratio of parent ion intensity to estimate relative quantities.

        It never panned out, but that was because our division was axed… my first layoff. You never forget the first time you get laid…. off, that is…

        -t

        1. Isidore says:

          I think the reason that initially, as you point out, peptides modified with the deuterated and non-deutertated ICATs co-eluted was poor chromatography, specifically poor resolution of “homemade” capillary HPLC columns. Once people doing better chromatography began using the reagents the lack of peptide co-elution was noted, which prompted the development of the C-13 version of the label.

    3. MTK says:

      Right.

      Proteomics guys I believe refer to the phenomenon as deuterium drag, since the deuterated peptides have a tendency to elute later than protonated ones.

      I’m not sure why this should be, but it is.

      1. anon says:

        Deuterium “drag”? According to Regnier (Anal. Chem. 2001, 73, 5142), “deuterated compounds [including peptides, which this paper was specifically concerned with] usually elute EARLIER than their nondeuterated counterparts in reversed-phase liquid chromatography.”

        1. 80085 says:

          Heh… Anal

        2. Zenboy99 says:

          Agreed. I’ve been in analytical chemistry for 17 years. I’ve always seen the deuterated internal standard for an assay elute earlier than the analyte.

        3. Istvan Ujvary says:

          Not to mention tritiated ones which are also more lipophilic than their 1H counterparts (if I recall correctly my HPLC purifications of 3H-labelled insect hormones ;-).

  5. Dan Brummett says:

    As a person who is not in any field related to chemistry I don’t understand why this development has taken so long. If the science of reaction rates involving hydrogen and deuterium has been established for quite some time why hasn’t the pharmaceutical industry taken advantage of this knowledge? This is exactly the kind of thing that makes a semi informed citizen like myself say, “This has a smell of over regulation about it” and then harbor, possibly unwarranted, ill will towards the FDA.

    1. Anon says:

      Good question. This has nothing to do with over-regulation as FDA has nothing against isotopes per se, as long as the drugs are shown to be safe and effective.

      More like pharma is entrenched in traditional medicinal chemistry thinking based on C, H, N, O and S, etc., combined with the fact that (a) the kinetic isotope effect is usually small and (b) deuterium is very expensive, so cost-benefit has been questionable until recently, when drug prices are going up and incremental benefits are getting smaller.

      In other words, it’s only becoming viable now because the overall economics of pharma are becoming so bad in general.

      1. Dan Brummett says:

        I did not realize deuterium was so costly. I’ve all ways assumed that the materials cost of drugs necessarily had to be next to nothing compared to the R&D cost in order to make this industry economically feasible. Does the cost of deuterium only come from purchasing or producing the material, or do products containing deuterium require more costly R&D?

        1. Some idiot says:

          Anon got there before me! 🙂

          Deuterium itself is more costly, and the number of molecular building blocks you can buy with deuterium in it is very small (relatively speaking), which in tern means the process research and development is generally a lot tougher, plus working with more expensive starting materials (and trying to get something with a lot of deuterium in it at a high level of enrichment can be far from trivial). Again, good question! 🙂

        2. Anon says:

          Drugs typically cost 5-15% of net sales price to produce (COGS), plus 20% of sales to discover and develop (total Pharma R&D spending is typically 20% of total sales), and 30-50% of sales for marketing, distribution and overheads, etc., leaving about 15-45% profit margin (much less for generics).

          Now 5-15% of sales for COGS doesn’t sound a lot, until you multiply by 10 or whatever for the cost of deuterium.

          1. tangent says:

            Do you happen to know a ballpark range of COGS for biologicals, for comparison?

        3. b says:

          The organic building blocks we use to make molecules ultimately come from 2 main sources: feedstock chemicals (i.e. petroleum products) and natural products (those produced by plants, bacteria, etc.), both relatively cheap. The main source of deuterium is heavy water, which is itself costly to produce. Add onto that derivitization to the necessary deuterated building blocks, the fact that it’s not trivial to put a deuterium anywhere you want in the molecule, the possibility of no benefit between the deuterated/protonated drugs in the clinic, and the fact that the IP surrounding deuterated drugs is risky (Derek’s brought this up around here multiple times before, like here), and the cost/benefit can tough to reconcile. I can assure you, it’s not the FDA.

          1. David says:

            Is it possible/plausible to create such raw material by feeding plants/animals exclusively on heavy water instead of normal water?

          2. AlphaGamma says:

            Replying to David:

            No,, because the kinetic isotope effect causes problems with biochemical reactions in an organism. Apparently mice die at around 50% substitution of hydrogen for deuterium, and the effect on plants seems to be similar.

        4. trinity says:

          It’s costly. I was on a program that got shot down real quick once process chem got involved. They estimated it be over 100k to make 10 grams of a deuterated drug. It was the deuterium reagent that ballooned the costs. What a shame, it was a remarkable compound that will never be developed.

          1. Pessinist says:

            David,
            Unfortunately not:
            At lower concentrations it’s will be rather noisily distributed on select products at select locations (so in theory there may be a case or two out there you may get lucky).

            At high concentrations it ends up being cell lethal; the slowing effect hits different systems disproportionally long before you get to satiation conditions.

          2. Mike says:

            It’s not the price of the deuterium making it prohibitive. Heavy water is about a dollar a gram, about 50 times less than platinum and they have no problem putting that in a drug. Just the research, that it is very different and that the drug is for a rare disease with a small market that likely held it back.

          3. Hap says:

            Tetradeuteromethanol is about $10/g (from Aldrich, all sizes), and things likely to be closer are likely more expensive than that. Pt drugs are generally not many steps from commercially available materials (and I think the Pt is installed late, so the expensive materials aren’t lost in most of the steps). (Cisplatin is about $400/g from Aldrich.)

            While trial and research costs are still likely to dominate drug costs, the cost of deuterium isn’t negligible (and the cost of D2O isn’t necessarily relevant to the drug cost).

    2. Some idiot says:

      Good question, but I don’t feel that the FDA is a cause for a delay. I broadly see two reasons:

      (A) deuterium is a lot more expensive than hydrogen. Therefore, in many cases it may be very expensive to put the deuterium where you want it to be. In the case here, deuterated methyl groups are relatively cheap. But still, you would need a damn good reason to use them instead of normal methyl groups. I am not familiar with the work here, but sounds like they have a good reason…!

      (B) patents… I would guess that the question as to whether swapping hydrogen with deuterium is novel according to the courts (although it sounds like in this case it should be). Because if the courts say that it is not novel, then you have no patent, in which case anyone can make and sell it…

      I would guess that there are a number of companies out there who were thinking about it, but decided that the significant extra cost wasn’t worth the risk of not being able to get (and keep) a patent. And again, I must stress that in very many cases, actually getting deuterium in the right place in the molecule will not be trivial…!

      1. Barry says:

        The U.S.P.T.O.’s test for patentability is three-fold. The innovation must be:
        -novel
        -utile
        and
        -non-obvious.
        So although a deuterated version of someone else’s drug would be novel, the patent examiner might still deny it a patent if she/he judged that it failed “non-obviousness”.

        1. Anon says:

          Problem is *everything* seems obvious in hindsight. Is it “obvious” that the deuterated compound would be more effective when its non-deuterated parent compound isn’t?

          I’m not sure there is enough medical history comparing the activity of deuterated vs non-deuterated drugs to say that the result in any one case would be predictable and obvious.

      2. Dan Brummett says:

        If a company took one of their drugs which was about to lose patent protection and replaced some key hydrogen with deuterium would that drug be eligible for patent extension? Would the new drug have to go through clinical trials?

        1. Some idiot says:

          Again, good question! My guess is the answer would be “depends, but probably not..”. There are a lot of different sides to the arguement, but when it comes down to it, you would need significant differences in activity (compared to the original) in order to convince people that it was better to buy this (expensive) drug than a (much, much cheaper) generic.
          Then there is the question of what you need to do in terms of clinical trials. If the activities are more or less the same, then you could probably argue your way out of some of the work. But by arguing that they are very similar, then you would probably be shooting yourself in the foot in terms of trying to get a patent on it… So my guess is you would probably need to run everything… But I don’t know what happened for this one, so I may well be wrong…!

        2. Anonymous med-chemist says:

          Different metabolism = different drug = new clinical trials. You do NOT alter metabolic profile and just assume the drug will work as an analog did. Well not unless you enjoy playing games with peoples’ lives.

        3. Derek Lowe says:

          It definitely would have to go through clinical trials, because you’d be trying to show an improvement versus the previously patented version (otherwise there’s no point). As for patent protection, this will eventually come down to “obviousness”, which is a standard that changes over time (as it has to). The other factor is that everyone recognizes the potential use of deuterated compounds now, and patent claims are written accordingly right from the start. The era where you could grab an old drug, deuterate it, and profit is already passing, and in fact, from an early research standpoint, has already passed.

        4. CTP-656 says:

          Yes it does, in fact there is an example in clinical trials (CTP-656) which has a non-deuterated version already on the market. See link in handle.

  6. G2 says:

    I would say it is ignorance from many colleagues & bosses regarding new territories (however the first deuterated analog was from Merck decades ago!). Nowagays in new patent filings you usually define that you can have deuerated versions also – so it is more difficult to obtain IP.

  7. Chris Phoenix says:

    Why did a request for more data (which already existed) cause a nine month delay? How much of the delay was actually finding the desired data in the dataset, and how much was paperwork / bureaucracy?

    1. anon says:

      Having data (i.e., having recorded something as part of an experiment and saved it somewhere), and using that data (i.e., extracting the bits you’re interested in and then evaluating that subset) are entirely different things. Data exists in huge piles. Most of the pile will describe parameters not relevant to answering your question of interest. Building the analysis that can sort out the relevant bits, maintain interrelationships, and leave out all the numerical parameters that aren’t relevant is a huge undertaking. 9 months doesn’t sound so long.

  8. Chrispy says:

    Great. Yet another high-tech, expensive route to me-too drugs that are just barely non-obvious enough to be patentable. (For now.) Luckily our broken medical reimbursement system allows charging obscene prices, even if the drugs are as marginal as this one. (Again: for now.) Teva plans to charge $60k a year for this stinker. So why waste your time trying to do anything novel when you can take a dirty drug from the 50’s, slap some deuteriums on it, and profit? The sheer waste in terms of opportunity cost, from medicinal chemistry development to manufacturing to clinical trials, is depressing. This whole industry is rapidly going down the tubes, victim of its own “successes” like this one.

    1. Some idiot says:

      I am 100% with you that what we need is new, useful, innovative drugs that actually help people, as opposed to things done _just_ to make money (ok, I am simplifying, but you know what I mean). But just because it has been approved, it doesn’t mean that people will pay for it, does it? I mean, do the payers really think that the difference in activity is enough to warrant the price? I don’t know, but time will tell

      1. cynical1 says:

        If you read his first link above, they are pricing it substantially cheaper than the generic non-deuterated tetrabenazine. So the patient would get a marginally better drug at a cheaper price than the generic. No down side there that I can see. And they did do the full trials, right?

        1. Chrispy says:

          $96k a year for generic tetrabenazine looks great when you see that Valeant is charging $152k a year for their brand-name version. This is a drug that has been around for decades. It is yet another example of price gouging, and it is unconscionable. If these funds were being channelled into research it would be somewhat more palatable, but they are instead channeled into executive pay, as are the savings from laid off researchers. It is such a deplorable situation: completely indefensible and unsustainable.

          1. cynical1 says:

            I couldn’t agree more. I am one of those laid off researchers. Several times and then got out. And, yes, it is unconscionable. So I have no naiveté regarding price gouging in the pharma sector. However, they are pricing it well below the other drugs for the indication and the market was sustaining the price before this post without public outcry. And MD’s won’t even understand how it differs from the non-deuterated drug anyway. So, this company introducing this “new” (read pathetic) drug with marginal efficacy improvements for a lower price actually doesn’t make them look particularly bad compared to the rest of the sector or the industry. Does it make pharmaceutical companies look bad in general? Well, yes it does. But the only goal of the industry is to increase shareholder value………until they don’t. That group called the FDA just stands in their way………until they don’t.

            I think you should now consider the pharmaceutical industry on par with used car salesmen. Because deuterating an old drug and bringing it to market is very, very, very much akin to that business. “Hey, we put new tires on an old car and now it’s new again.”

            It’s okay. It’s making America great again. Haven’t you noticed?

  9. BK says:

    It was shown somewhere in literature that if one were to substitute methyl esters on cocaine to methyl ethers, the compound lasted significantly longer in vivo. The organic chemist in me wonders if the deutero methyl variant would last even longer now…

    1. NJBiologist says:

      The enzymes that break both of those esters are both esterases (butyryl- for the phenyl ester, and carboxyl- for the methyl ester). I don’t think those break ethers at all, so I wouldn’t expect a further isotope effect (but I could be wrong about esterases and ethers…).

  10. David says:

    “…another neutron”? Do you mean “a neutron,” or have my highschool science memories failed me? I thought plain hydrogen had one proton and no neutrons, deuterium one neutron, and tritium two?

    1. Goat sea says:

      One is ostensibly ‘another’ more than zero.

  11. David says:

    Maybe this is obvious, but is this something that could prolong the effectiveness, or increase the effective strength, of more mild painkillers such as paracetamol, lower dose codeine? Could it increase the ability to kill pain, or length of such effects, at a lower or less frequent dose, and thus be a measure against the addictiveness of opiates, etc?

    1. Barry says:

      This approach is mostly going to increase the exposure of a drug that is primarily cleared by a process involving C-H bond cleavage. The particular Teva example is actually a bit of a freak; the bond broken is C-O, and the C-D bonds are only secondarily involved.
      Paracetamol is removed by sulfation; you would expect no effect for deuteration.

      1. Derek Lowe says:

        The first metabolite is via reduction of the CO, and that gives an active species. Further metabolism of that one, though, is what the deuteration slows down, and that does involve C-H bond effects.

        1. David says:

          Fair enough – I’m obviously not familiar with the biochemistry/metabolisation of any drugs!
          Are there any potential benefits along the lines I was suggesting, re effectiveness/duration and anti-addictive possibilities?

          1. ChemistryFunny says:

            Not dissimilar to the deuterated DDT comment farther down this thread, deuterated morphine was looked at back in the early 60s (Elison, C. et al. Science, 1961, p1078 DOI: 10.1126/science.134.3485.1078). The authors suggest that while the CD3 undergoes slower demethylation in microsomes, it is a less potent compound although appears to have a similar TI with certain routes of admin. They only postulate that the DOA should be the same; there may be follow-up papers that cover this in more detail.

  12. John Campbell says:

    Deuterated analogues of drugs would usually be made as part of ADME studies and sometimes are mentioned in patents, so I don’t know how easy they would be for someone else to patent. Interesting article, if only for its title here: http://www.fpapatents.com/resource?id=452 although it never really gets to grips with the patentability problem.

  13. Medchem Bystander says:

    All of you keeping going on about “obviousness” and “patentability”. This approach is yielding plenty of IP. Just check out this page from Concert Pharmaceuticals’ website:

    http://www.concertpharma.com/technology-overview/intellectual-property/

    1. Derek Freyberg says:

      Yes, and Sepracor had a nice portfolio of patents on isolated isomers of racemic drugs too (not infrequently on each of the two isomers for assertedly different uses).
      Patents do not equal drugs.

  14. Xiao Bu says:

    Question for IP people – does legal precedent exist in patent law? And if it does, could you rebut a challenge of “obviousness” based purely on the fact that companies before have successfully patented compounds that are only distinguished from known drugs by a deuterium atom?

  15. will says:

    To overcome novelty, you have specify the isotopic enrichment to a point greater than the natural abundance of deuterium

    For obviousness, you’d probably need to show (a) it was recognized that the carbon-hydrogen bond in question was in some way implicated in the activity of the compound, and that there was a reasonable expectation that replacing with deuterium would give an expected improvement (b) that a chemist could make the deuterated compound without undue experimentation (easy enough for deutatetrabenazine , but maybe not always) After that it would come down to how much better it worked, unexpected results etc.

  16. David Borhani says:

    Feeling too lazy to look myself: Does anyone happen to have a link to Teva’s process for production of the drug? (Presumably a patent(s)?) Thanks.

      1. David Borhani says:

        Thanks. I did some more digging: I think this is the process patent: https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015084622

        Chengzhi Zhang, “Methods of manufacturing benzoquinoline compounds as inhibitors of vesicular monoamine transporter 2 (VMAT2)”

        CD3 groups get put on to catechol with CD3I (yield ~100%); then Vilsmeier-Haack to close up to the dihydrohydroisoquinoline; then alkylation/ring closure to tetrabenazine. Pretty efficient,

  17. mallam says:

    Find it necessary to make two points. The deuterium (and tritium) isotope effect has been well known for decades as demonstrated by use in enzyme mechanistic studies. Those of us who are well versed in such work do not find this approach novel from a scientific perspective, it’s been discussed for much longer than the existence of Concert, eg comment of Merck compound above. Other attempts using various hypotheses ultimately failed.
    Also, the lack of obviousness for successfully patenting deuterated drugs would come from the unpredictability nature of such approaches. Many compounds when deuterated will not show a useful difference between the natural isotope, and hence the demonstration of a positive difference in outcome should be sufficient to satisfy this requirement.

    1. Mol Biologist says:

      Agreed and one more push-back from naysayer, Adding deuteriums do no not resolve neither depression and suicidal behavior neither huge metabolic imbalance brought by expansion of repeats of the trinucleotide CAG in exon 1 of the HD gene. which encodes for the protein huntingtin. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4097094/

  18. gippgig says:

    H-C=O-H in a cryogenic matrix has a half-life of about 2 hours for rearrangement to formaldehyde while H-C=O-D is stable (calculated half-life of over 1000 years). Apparently a quantum effect, of course. Nature Vol. 453 page 906

    1. tangent says:

      o_O
      Where are the electrons on that puppy, and why does it have any interest in existing?

      1. gippgig says:

        Think of HCOH as reduced carbon monoxide.

        1. tangent says:

          Fair, I can’t say I understand carbon monoxide either. Why so stable when the polarity is fighting against the electronegativity?

        2. senilechemist says:

          The structure should be H-C-OH, the carbene hydroxymethylene.

  19. Anonymous says:

    (1) Another D-drug is from Alkeus Pharm, Josh Boger, founder and former CEO of Vertex, is Exec Chairman. They are deuterating the C20 methyl group of Vitamin A to slow down the formation of A2E and related pigments to slow the progression of vision loss in patients with Stargardt Disease, I think one problem is limiting dietary intake of protio-carotenes and protio-vitamin A.

    (2) I think there was a D-shortage and price increases in the 90s when one or more US production facilities were shut down. That also might have slowed down the R&D of D-drugs. Does the US produce any D2O at all anymore? Canada still produces D2O for their CANDU reactors and is still a good source.

    _Fugue For Tinhorn Analysts_
    I got the drug right herium, it’s got a good deuterium,
    And the CEO says that the trials are in the clearium,
    CANDU, CANDU, the CEO says the drug CANDU
    If the FDA says this drug CANDU, CANDU, CANDU.
    https://www.youtube.com/watch?v=jU0PdpqDB88

  20. Tony Czarnik says:

    It’s been a continuing disappointment to hear the negativity regarding new approaches to drug discovery coming from medicinal chemists. Biologists don’t do this; their work leads to startups. We chemists need to invent new methods that lead to patentable molecules with useful properties. Or we really may be replaced with robots one day. Don’t laugh.

    Infringement lawsuits based on, “obviousness?” Patent court begins with a finding that the decision of a Patent Examiner leading to an Issued patent is correct. The burden of proof lies with the Plaintiff. After 10 years of the USPTO working through the H/D issue, the lack of obviousness will be easy to demonstrate.

    By the way… first deuterated drug- Rapoport in 1961.

    https://www.ncbi.nlm.nih.gov/pubmed/13889855

    Intent was to slow demethylation. It did that, but lead to both decreased binding and undesirable metabolic side-products.

    1. Dr CNS says:

      You know, Tony, this is happening in many areas, and to a point it is expected.
      New knowledge always comes with push-back from naysayers.

    2. Istvan Ujvary says:

      Why don’t we call them D-too-drugs?

      Actually, deuterated DDT was made in 1959 (or so) by reacting deuterochloral with chlorobenzene: Barker: Syntheses of the Aliphatic Deuterium Analogs of DDT and TDE and
      Their Toxicity and Degradation When Applied to Adult House Flies
      Quote from this papper:
      “In enzymatic reactions, deuteration reduced activity about 30% with acetyl choline (Erlenmeyer & Lobeck 1937), succinic acid (Erlenmeyer et al. 1936, Sonderhoff & Thomas 1937, Thorn 1951), formate (Kuchinskas et al. 1959), and acetate (Sonderhoff & Thomas 1937).”

      https://academic.oup.com/jee/article-abstract/53/1/35/802415/Syntheses-of-the-Aliphatic-Deuterium-Analogs-of?redirectedFrom=fulltext

  21. Curious Wavefunction says:

    I am assuming that every time there is a chance that a C-H bond in a phenol will get hydroxylated and then eliminated through glucuronidation, deuterating that bond would help. The balance of PK would of course depend on the particular context.

  22. Steve says:

    Regarding ‘obviousness’: Is it obvious that deuteration of a particular part of a molecule will give a particular enhancement (usually exposure)? Certainly not in my experience. I’ve tried this many times on a raft of different molecules which could stand to benefit from reduced metabolism to find that only in very few cases (one actually) did this give marked increase in exposure. Certainly the concept is obvious (and should be tried more routinely), but whether the effect actually works in practice is not obvious.

  23. J. says:

    What happens to the deuterium after the liver has done it work? Will it be excreted or integrated into the body? Couldn’t that disturb important biochemical processes?

    1. Druid says:

      Your body water is already 160ppm deuterated – about 4 to 7 grams just in water. Tests have been done giving deuterated water at 300mg/kg body wt, so about 25g D2O to volunteers. This was done to quantify total body water, so that much has no ill-effects. If the deuteration of O-methyl prevented all metabolism by that route, then the drug has to be cleared some other way, taking the deuterium with it, but in fact the D3CO- group is still metabolised, just more slowly, so the products will be HDO – a drop in the ocean of what is already there – and d2-formaldehyde which will be further oxidized to deuterated water and carbon dioxide.

  24. loupgarous says:

    Tritiated octreotides are another target – they’d deliver a big knock to neuroendocrine cancers, bond more tighly to them than standard octreotides.

  25. Druid says:

    Metabolic breaking of a C-D bond is rarely the rate-determining step (which is probably electron abstraction, or simply binding to the CYP) so there are no 7-fold improvements as you can get chemically. In this case, the dose adjustment for switching from tetrabenazine to deutetrabenazine is approximately two-fold, which is a typical best case for deuteration.
    What really surprises me is that this new product is a racemate, and on top of that the assays for parent compounds and metabolites are not enantio-selective.
    Furthermore, considering that tetrabenazine and its reduced metabolites are all substrates of CYP2D6, and that the deuterated isotopomers also bind to CYP2D6 but are metabolised more slowly, why have they not been tested for CYP inhibition, even in vitro?

  26. LKB says:

    Late comment here. Let’s say you deuterate a hydroxyl group that is normally targeted for glucuronidation. Would you expect O-D to be less susceptible to glucuronidation than O-H?

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