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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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February 17, 2009

Heavy Atoms, Heavy Profits?

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Posted by Derek

Carbon 12, nitrogen 14 – for that matter, hydrogen 1. Everyone who’s had to study even a bit of chemistry has had to learn the molecular weights of the elements, figure molecular weights from formulas, and so on. But these numbers aren’t quite as round and even as they look, and the consequences of that are sometimes surprising. And at the moment, at least three companies are trying to turn the whole idea into a huge amount of money.

My scientific audience will have guessed immediately that I’m talking about isotopes (although some of them may well be wondering where the pile of money comes into it). For those who don’t make a living at this sort of thing and have put such topics out of their minds, it’s the number of protons in an atom’s nucleus (the atomic number) that determines what sort of element it is. Carbon, for example, always has six protons. But there are neutrons in there, too, and those can vary a bit. Six protons and six neutrons gives you a nucleus of carbon-12, which is the most common. But one out of every hundred or so carbon atoms has seven neutrons instead of six: C-13. That’s a perfectly stable isotope of carbon, and is much beloved by chemists for its behavior in NMR experiments. If you push that neutron count too far, though, you get unstable radioactive nuclei. That’s where the famous carbon-14 comes into the picture (six protons, eight neutrons). You can have carbon-11, too, although it’s pretty hot stuff. Hydrogen, for its part, has the usual one-proton nucleus in its most common form, a one-proton-one-neutron stable form called deuterium, and a radioactive form with two neutrons called tritium, found in isotope labs and the innards of hydrogen bombs).

Radioactive isotopes have a long history in medicine and biochemistry, both as therapeutic agents (for cancer) and as tracers. But what about stable isotopes? Until recent years, not as much. But modern mass spectrometry machines are so good at what they do that they’ve eaten into a lot of the applications that used to be reserved for radioactive isotopes – more on that in another blog post; there are some ingenious tricks there. And those three companies I mentioned are trying to take advantage of yet another property, known as the kinetic isotope effect.

Imagine a bond between a hydrogen and a carbon as being between two metal balls, one of them twelve times as heavy as the other, connected by a spring. This is about as simplistic a picture of a carbon-hydrogen bond as you could possibly come up with, but for this purpose that model works disconcertingly well. Imagine then replacing the smaller ball with one that weighs twice as much as the original one; that’s a replacement of hydrogen with deuterium. Now, how will the behavior of that springy system change?

Well, that’s sophomore physics, weights and springs, and that’ll tell you that it’s now harder to twang the second system around. We see that exact effect in chemistry. A carbon-deuterium bond breaks about six or seven times slower than a carbon-hydrogen bond under room-temperature conditions. So where exactly is the big money in this effect?

Consider what happens to a drug when it’s ingested. Through the gut wall it goes, into the hepatic portal vein, and directly into that vast shredder we know as the liver. Various enzymes go to work tearing your unrecognized drug structure apart, the better to sluice it out through the kidneys as quickly as possible. And there’s the opportunity: a great many of those enzymatic reactions involve breaking carbon-hydrogen bonds. What if they were deuteriums instead?

That’s what Auspex, Protia, and Concert Pharmaceuticals are all working on. They’re taking existing drugs, whose metabolic fates are known, and battening their structures down with deuterium atoms in hopes of improving their half-lives and general behavior. And thus far, the idea seems to be working out. Auspex announced last fall that they'd seen good results (PDF) in the clinic with a deuterated version of venlafaxine (brand name Effexor, a well-known antidepressant. Concert, for their part, has announced that they've improved the antibiotic linezolid, sold as Zyvox. Protia - well, as far as I can see, Protia has been very quietly filing patents on deuterated versions of every big-selling drug that they can think of. What they're doing in the lab seems to still be under wraps.

Is this going to work? Good question. To a first approximation, you'd think it probably would, particularly for drugs whose main liabilities are poor pharmacokinetics (or side effects driven by a particular metabolite). But there are complications. For one thing, deuterium is not completely innocuous in vivo. I strongly doubt that the dosages of deuterated pharmaceuticals could present any kind of problem, but if you load up a higher organism with exchangable deuterium, trouble ensues. For humans, it would seem that you could, in theory, go a week or so on a few liters a day of straight deuterated water before you'd have to worry, which is nonetheless an experiment that I would strongly discourage. So the amount of deuterium picked up through metabolism of a prescription drug should have no effect - but there's always the possibility that the FDA, in its risk-averse mode, might make you jump through some extra hoops to prove that.

Another (much more real) risk is that the whole strategy will burn itself out. Clearly, the existing startups are working off the fact that no one has traditionally bothered to claim deuterated versions of their patented compounds. That is surely already changing, and if something hits the market it'll change big-time, reminiscent of Sepracor's old business model of grabbing unclaimed metabolites and enantiomers. And, of course, the three companies in this space are surely already throwing elbows into each other's IP space already.

But there's still a window of opportunity, and these folks are going for it. Isotope effects could end up being rather more immediately valuable than anyone ever knew. . .

Comments (31) + TrackBacks (0) | Category: Drug Development | Pharmacokinetics


COMMENTS

1. aa on February 17, 2009 9:33 AM writes...

great post... just the kind of stuff that keeps coming back to your site.

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2. milkshake on February 17, 2009 9:55 AM writes...

Deuterated chloroform is supposedly noticebly less toxic than normal chloroform, because of its slower metabolism in liver and kidneys.

I was also thinking about deuterating drug candidates with a marginal PK in hopes of improving the half-life slightly. Many per-deuterated building blocks are available for reasonable price, and there is number of good method for making selectively deuterated stuff. Deuterium toxicity should not be a problem - about 1% of all hydrogens in our body are deuterium, and the tests with lab animals and plants fed D2O did not observe toxic effects until the deuterium levels in vivo reached about 70%.

(Apart from deuterium, other stable heavy isotopes are much less promising - except for some special diagnostics done by MRI - because the isotopically-pure starting materials are very expensive and the kinetic isotope effect is likely to be very small for atoms like C, N, O.)

As for claiming IP property, it takes very little to write patent applications full of prophetic examples, and all small companies advertise their "proprietary technology platform" regardless of whether it actually works.

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3. Petros on February 17, 2009 10:20 AM writes...

A few years back there were two of three companies doing Si for C switches in known drugs (Amedis was one at the time). That all seemed to die a death

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4. Ed on February 17, 2009 10:34 AM writes...

Wouldn't a rather nefarious purpose for this be in performance enhancing drugs? Are deuterated analogues already banned? Are they even detected by modern testing, which I guess is mass spec dependent?

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5. milkshake on February 17, 2009 11:19 AM writes...

There are easy methods for random partial deuteration of molecule all over, including the non-activated aliphatic sites - for example refluxing the parent with Pd-C in D2O. Having a mix of randomly labeled anabolic steroid containing anything from 1 to 15 deuteriums per molecule would considerably broaden and decrease the MS signal and make it look very much like an artifact from contamination. It could make thing undetectable or some borderline positive tests disputable - until dope-testing methodology catches up.

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6. weirdo on February 17, 2009 11:32 AM writes...

This is the penultimate approach to "me-too" drug-design. And it's not coming from an evil "Big Pharma". It's coming from those highly innovative, deep-thinking biotechies. Where's Marcia Angell when you need her?

Ah, what a wonderful industry in which to work . . . .

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7. SteveM on February 17, 2009 11:40 AM writes...

Given the this topic and the topical nature of the Stimulus Leviathan, here's a replay of the classic and timely abstract describing the unusual atomic species "Governmentium"

A major research institution (MRI) has recently announced the discovery of the heaviest chemical element yet known to science. The new element has been tentatively named Governmentium. Governmentium has 1 neutron, 12 assistant neutrons, 75 deputy neutrons, and 224 assistant deputy neutrons, giving it an atomic mass of 312. These 312 particles are held together by forces called morons, which are surrounded by vast quantities of lepton-like particles called peons. Since governmentium has no electrons, it is inert. However, it can be detected as it impedes every reaction with which it comes into contact. A minute amount of governmentium causes one reaction to take over four days to complete when it would normally take less than a second. Governmentium has a normal half-life of three years; it does not decay, but instead undergoes a reorganization in which a portion of the assistant neutrons and deputy neutrons exchange places. In fact, governmentium's mass will actually increase over time, since each reorganization will cause some morons to become neutrons, forming isodopes. This characteristic of moron-promotion leads some scientists to speculate that governmentium is formed whenever morons reach a certain quantity in concentration. This hypothetical quantity is referred to as Critical Morass.

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8. Sili on February 17, 2009 11:47 AM writes...

Off-topic-ish, but I seem to recall that natural variation in isotopic frequensies is already used to trace cocain. Apparently it's possible to link the N/C/O distribuations to particular soils.

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9. Jose on February 17, 2009 12:16 PM writes...

I was unfamiliar with the name Marcia Angell; Wiki has some truly jaw dropping quotes from her. *Harvard* and NEJM are providing a soapbox for such truly ill informed idiocy??? Why doesn't the ACS (or evil twin the ACC) get a decent PR machine going and bulldoze her into the trash bin??

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10. SRC on February 17, 2009 12:32 PM writes...

I always wondered why no one was trying to exploit the kinetic isotope effect to improve PK and thereby make an old drug patentable again. Several of us were musing on this very notion a number of years ago.

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11. SP on February 17, 2009 12:35 PM writes...

Meh, from what I've heard the PK stuff is a fig leaf to show some kind of utility, the real purpose was patent busting.

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12. Hap on February 17, 2009 1:03 PM writes...

Jose - two words re Harvard: "Harvey Mansfield". There's lots of good people there but also some real "winners". (Heck, HM might have been good once, but by the time I was in the vicinity, his job seemed to be primarily to be annoying and conservative, preferably without any reference to logic. History classes with him would have been a blast, if projectile vomiting is fun.)

The NEJM, well, they don't seem to have covered themselves in glory lately.

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13. bad wolf on February 17, 2009 1:18 PM writes...

#9 Jose--I just looked at the wikipedia for her also and i'm not sure i see your disagreement. "Critic of US Healthcare", "Critic of Pharmaceutical industry" and "Critic of Alternative medicine" all describe pretty much everyone commenting on this blog, for one.

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14. CMC Guy on February 17, 2009 3:43 PM writes...

This seems to be one of those circular ideas as making Deutro-drugs was contemplated about 20 years ago in a company I worked at. Besides latent toxicity uncertainty (and getting FDA to buy into not unknown trouble) there were concerns about cost differential (D-analogy likely slightly more and Patented Intermediates blocking routes) and IP issues (obviousness criteria hard to make concrete). Like may drugs there may be certain possible benefits over other related but still a considerable challenge that not as straight as some would like to believe. Certainly did not pass Big Pharma internal assessments and would take a definite Biotech rogue approach.

Unfortunately Angell is not alone in her view(s) and with other conflict of interest dogmatics have created a popular perspective that "evil" Pharma is only exploitative and not making contributions so anything they touch is bad. Lots of problems out there no doubt but in the main would suggest majority of people/companies are there for the expressed purpose of using their skills with end goal to help people/society.

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15. BenchSlave on February 17, 2009 5:20 PM writes...

I don't think this really stacks up as a strategy for new patentable versions of old drugs as most patents claim isotopic variants of the compounds claimed anyway. You could make an inventive argument about a deuterated compound but you're not going to address the issue of novelty. In so far as I understand it ...

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16. ... on February 17, 2009 5:49 PM writes...

I work with a synthetic group in academia and we just started collaborating with a group in biology. They'll be including our compounds in their high-throughput screening. I've got a bunch of amines. Should I submit my samples as the free-base or as a salt? Does it make sense to make five different salts (e.g. hydrochloride, citrate, sulfate, etc.) or is there a good default anion?

Thanks for any help you can offer.

Loved the post Derek!

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17. milkshake on February 17, 2009 6:38 PM writes...

I have to correct myself - I just checked the deuterium natural abundance and it is actually much lower than I thought, only 150 ppm on molar basis. 1% is the abundance of carbon 13

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18. drug_hunter on February 17, 2009 6:43 PM writes...

Re: Angell: Her writing is bilious and she is painfully shrill in person. And, in fact, not very bright. No real solutions to any of our problems, just cashing in on the current dilemmas we all face.

Re: deutero-bottom fishing: interesting to see how claims like these will hold up in the face of the new, tougher patenting standards. I certainly wouldn't be betting much on these boutiques.

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19. Pat Pending on February 17, 2009 8:39 PM writes...

"I don't think this really stacks up as a strategy for new patentable versions of old drugs as most patents claim isotopic variants of the compounds claimed anyway. You could make an inventive argument about a deuterated compound but you're not going to address the issue of novelty. In so far as I understand it ..."

I think in a post KSR world you might have a hard time convincing the PTO and then a federal judge that a deuterated analog of a known drug is not obvious absent some form of unexpected results. Especially since you would know, based on metabolism studies, where you wanted to place the deuterium to inhibit metabolism.

In fact, you might find yourself in the position where you have trouble getting the drug approved by the FDA and then seven years later have generics knocking on your door when your exclusivity expires.

I seem to remember that pesticide chemists wanted to make a deuterated form of DDT 30 years ago where the compound would be deuterated next to the trichloromethyl group to slow detoxification by resistant flies.

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20. Polymer Bound on February 18, 2009 12:53 AM writes...

Reminds me of a paper I saw presented in grad school (maybe by Vedejs?) where they used deuterium as a lithiation blocking group. Wacky stuff.

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21. AliG on February 18, 2009 8:08 AM writes...

#16
You should only need to submit one version for testing. Free base or salt shouldn't make a difference. You should pick the one that gives you a nice solid that is easy to weigh out, if possible.

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22. MTK on February 18, 2009 8:57 AM writes...

Color me skeptical on this one.

Preclinical or Phase I pharmacokinetic data is one thing, real clinical benefit is another. I guess if you can go from b.i.d. to u.i.d. that would be enough as long as everything else stayed relatively constant.

Even if the idea does work great, I'm not sure you would save a lot in terms of development costs. Despite the fact that these are deuterated versions of approved compounds, would not much of the clinical trials have to be repeated given they are new chemical entities with different properties? Would not toxicity testing have to repeated since they are different compounds made from different routes with different impurity profiles?

I guess what I'm getting at is that this seems a lot different than just a change in a formulation or going from racemate to single enantiomer.

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23. MTK on February 18, 2009 9:28 AM writes...

Color me skeptical on this one.

Preclinical or Phase I pharmacokinetic data is one thing, real clinical benefit is another. I guess if you can go from b.i.d. to u.i.d. that would be enough as long as everything else stayed relatively constant.

Even if the idea does work great, I'm not sure you would save a lot in terms of development costs. Despite the fact that these are deuterated versions of approved compounds, would not much of the clinical trials have to be repeated given they are new chemical entities with different properties? Would not toxicity testing have to repeated since they are different compounds made from different routes with different impurity profiles?

I guess what I'm getting at is that this seems a lot different than just a change in a formulation or going from racemate to single enantiomer.

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24. Chrispy on February 18, 2009 3:26 PM writes...

#16

If this is for animal testing sometimes the HCl salts are more irritating. If you "deliverables" are by weight and you come up a little short make the tosic acid salt to add a bit of mass. Free bases are often more difficult to get dissolved in water than are their corresponding salts. As ALiG alluded to above, different salts will have different physical properties and it is nice to have a crystalline solid to deal with.

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25. Larry on February 18, 2009 3:35 PM writes...

Re: Comment 20

That Vedejs paper is JACS 2002 124 748.

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26. weirdo on February 18, 2009 5:15 PM writes...

Chrispy,
Are you suggesting your biologists dose by batch weight and not salt-corrected weight?

Damn, you really need new biologists.

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27. milkshake on February 18, 2009 9:05 PM writes...

no, but the screening managers decide on some arbitrary minimum amount of material required for the submission.

We don't have this kind of problem here - our chemists supply their test compounds as 10 mM stock solutions in DMSO, and the screening wants only 0.2mL of it, so you do fine as long as you have enough material for 0.2 mL of the stock

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28. Other deuterium sightings on February 18, 2009 10:10 PM writes...

Sam's synthesis of guanacastepene displays a practical use of the D effect, and there is also a synthesis of norzoanthamine (Miyashita?) for selective oxidation.

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29. Anonny mousE on February 21, 2009 8:21 AM writes...

As for post 3, the Si switch is still on-going (look up West and indomethacin analogue for pancreatic cancer).

As for D, I made a CD3 analogue of a drug that we were developing as a Mass Spec marker for metabolism studies. It later transpired that the half life was increased 50% compared to the straight Me as glucuronidation of an adjacent site was being slowed.

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30. j cai on February 26, 2009 5:44 AM writes...

this has been investigated in 60s and 70s, reviewed and concluded as "not working".
I had the same idea 4 years ago, I thought that it was a "billion dollar" idea after consulting my PK collagues, as soon as I searched literature, I gave it up in milli-seconds for two reasons 1) not new 2) not working.

Some start-ups might claim it for an IP (questionable) position, but...

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31. just a thought on March 11, 2009 1:33 AM writes...

If undesirable metabolites are a problem then deuteration is not going to help *them* dissipate any quicker either! and would probably just make things worse...
Although, I guess it depends on whether or not the side effects are through chemical or structural interactions...

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