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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: Twitter: Dereklowe

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May 7, 2013

An Update on Deuterium Drugs

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Posted by Derek

In case you're wondering how the deuterated-drugs idea is coming along, the answer seems to be "just fine", at least for Concert Pharamaceuticals. They've announced their third collaboration inside of a year, this time with Celgene.

And they've got their own compound in development, CTP-499, in Phase II for diabetic nephropathy. That's a deutero analog of HDX (1-((S)-5-hydroxyhexyl)-3,7-dimethylxanthine), which is an active metabolite of the known xanthine drug pentoxifylline (which has also been investigated in diabetic kidney disease). You'd assume that deuteration makes this metabolite hang around longer, rather than being excreted, which is just the sort of profile shift that Concert is targeting.

Long-term, the deuteration idea has now diffused out into the general drug discovery world, and there will be no more easy pickings for it (well, at least not so many, depending on how competently patents are drafted). But if Concert can make a success out of what they have going already, they're already set for a longer term than most startups.

Comments (15) + TrackBacks (0) | Category: Pharmacokinetics


1. newnickname on May 7, 2013 8:01 AM writes...

Josh Boger, former CEO of Vertex, has joined Alkeus Pharm (in Cambridge, MA) as Executive Chairman. One of their leads is C20-trideutero-Vitamin A:

C20-D3-vitamin A Slows Lipofuscin Accumulation and Electrophysiological Retinal Degeneration in a Mouse Model of Stargardt Disease. J Biol Chem, 2011, 286(10), 7966-74.

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2. Anonymous on May 7, 2013 8:41 AM writes...

Can anyone explain the rules on this yet ?

I've put CD3 in place of CH3 (and CD2CD2OH in place of CH2CH2OH) in sites that we knew were the primary metabolic site and seen no effect in vitro.

Then there are cases where there is an effect in vitro, but this doesn't translate in vivo (Bioorganic & Medicinal Chemistry Volume 21, Issue 11, 1 June 2013, Pages 3231–3239)I'm only going on the abstract here so don't know how big the in vitro effect was.

Surely if it was purely a classical deuterium isotope effect this would be independant of substrate and would translate from in vitro to in vivo (assuming the same mechanism)

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3. A Nonny Mouse on May 7, 2013 8:51 AM writes...

I made a CD3 change for MS metabolism studies about 25 years ago; we found that it lasted about 50% longer than the CH3 compound though metabolism was occurring on an adjacent nitrogen atom.

Must confess that we never thought about having this as the final drug substance (bombed out anyway.....).

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4. Sideline Chemist on May 7, 2013 9:24 AM writes...

The location of the D has to be involved in the rate-limiting step of the metabolism and the site of metabolism within the molecule has to be very conserved (usually with more polar compounds).

Broad application to lipophilic compounds can be difficult because often the observed site of metabolism is simply the lowest energy site of oxidation. D replacement may have no affect because H abstraction isn't the rate-limiting step in the metabolic cascade. Or you might actually be having an isotope effect on the H abstraction from that carbon, but the CYP just moves to the next lowest energy well and oxidizes the molecule somewhere else equally as fast. Treading that murky landscape can send you into attempts to deuterate every carbon atom in the molecule trying to find the rate-limiting spot.

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5. watcher on May 7, 2013 10:34 AM writes...

I don't know how Concert can have a wide, general patent in this area as the concept of using isotope labeling to change metabolism has been around for decades. Anyone care to comment?

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6. SP on May 7, 2013 11:16 AM writes...

5- They don't, they patent the deuterated forms of several compounds but it's a case by case basis. Since everyone in the future will patent the D forms as well, as Derek says they'll have a hard time making that play in the future.

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7. a. nonymaus on May 7, 2013 11:25 AM writes...

Re: 2
Perhaps you need more kinetic isotope effect, tritiate the compound. What could possibly go wrong?

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8. watcher on May 7, 2013 11:36 AM writes...

#2: #4 is essentially right. The deuterated position(s)would have to be in locations where the respective metabolism is slowed enough to have in impact on the total in vivo clearance. A switch to alternative clearance pathway(s) will trump the isotopic effect.

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9. Darwinsdog on May 7, 2013 3:20 PM writes...

OK patent boilerplate tends to cover isotopes now as a precaution to this kind of opportunism but it has always struck me as odd that it could be allowed (and I don't know to what extent it has been challenged). Sure composition-ally hydrogen and deuterium are different but isotopic distribution is really what we are talking about here and for the sake of arguement as well as a nod to reality it doesn't have to be 100% enriched when we decide to rendor a Markush with an "H" or a "D" so in that sense I don't know where one draws a line for a claim. Not to worry though our favorite patent office west of the Himalayas won't care.

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10. gippgig on May 7, 2013 8:15 PM writes...

I remember reading one of those new wonder drug stories decades ago about a combination of the old drug cycloserine and, as I recall, 2-deutero-3-fluoroalanine. As far as I know, as is typical for these stories, nothing ever came of it.

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11. Mia on May 7, 2013 10:07 PM writes...

9. The thing is- Concert pharma put the money and research into pitting deuterated versions against their existing counterparts and came out on top. Their research proved that deuerated versions of some existing drugs behaved differently enough to be patented as a new and improved compound.

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12. weirdo on May 8, 2013 9:25 AM writes...

11-Mia -- Until we see one of Concert's issued patent claims challenged in court, your statement is a bit far-reaching. "proved" is a bit strong. "claimed" is more accurate.

"unexpected" is yet another hurdle. I'm not sure what, exactly, is unexpected about an isotope having a different metabolic profile.

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13. petros on May 9, 2013 7:10 AM writes...

#12 has it right. Sepracor, with its patents on enantiomers, also had to slug it out in the courts if its products become interesting enough for it to be worth doing so.

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14. silverpie on June 10, 2013 12:28 PM writes...

#4: "but the CYP just moves to the next lowest energy well and oxidizes the molecule somewhere else equally as fast"

That may be useful--if you chop the molecule at a different point, wouldn't you get different metabolites, which could be better or worse than the original?

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15. Saradhi Bolli on August 14, 2013 1:33 AM writes...

I am Saradhi from Neuland Labs India. Neuland provides process development and API manufacturing service on contract basis. We have experience in process development and manufacture of deuterated APIs (NCEs). We have license to import deuterated RMs, license to manufacture deuterated APIs in India and license to export deuterated APIs. If you want your deuterated APIs to be developed and manufactured, please do contact me. Thank you, Saradhi Bolli,, +919966030784

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