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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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« AstraZeneca Tears 'Em Down | Main | Just A Few More Month's Work, That's All I'm Asking Here »

April 27, 2011

Off the Beaten Track. Way, Way, Off.

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Posted by Derek

Now here's a structure that you don't see every day. A company called RadioRx is developing compounds as radiotherapy sensitizers for oncology, designed to release reactive free radicals and intensify the cell-killing effects of ionizing radiation. And these compounds are not from the usual sources. As they put it:

In collaboration with a major defense contractor, RadioRx is developing its first lead candidate, RRx-001, a best-in-class small molecule, adapted from an energetic solid rocket propellant. The development candidate is scheduled to enter first-in-man phase 1 clinical studies by Q1 2011.

I've been forwarded a report that this is the structure of their compound, which would make their defense-contractor partner Thiokol (the assignee where that compound appears in the patent literature). (Here's one of RadioRx's own patents in this area). And I truly have to salute these guys for going forward with such an out-there structure. Can anyone doubt that this is the first gem-dinitroazetidine to reach the clinic? And with a bromoamide on the other end of it, yet?
dinitro.png
It's easy to look at something like this and mutter "Only in oncology", but at the same time, it takes some nerve and imagination to go forward with compounds this odd. I hope that they work - and I hope that everyone else looks at their own chemical matter and decides that hey, maybe there's more to life than Suzuki couplings and benzo-fused heterocycles.

Comments (27) + TrackBacks (0) | Category: Cancer | Drug Development


COMMENTS

1. BFS on April 27, 2011 9:44 AM writes...

Wonder how "energetic" it is?

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2. Synthesist on April 27, 2011 9:53 AM writes...

I wouldn't fancy heating it too hard......

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3. You're Pfizered on April 27, 2011 9:53 AM writes...

"I hope that they work - and I hope that everyone else looks at their own chemical matter and decides that hey, maybe there's more to life than Suzuki couplings and benzo-fused heterocycles."

Totally unfair. I do plenty of amide couplings and SnAr's as well...

;)

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4. Hap on April 27, 2011 10:01 AM writes...

That bromoamide looks kind of activated - maybe that's the point, but I can see why someone might be hesitant to want it around.

I guess if this hits the big time, it'll be shipped by ground only?

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5. anon on April 27, 2011 10:21 AM writes...

entering into clinical trials isn't the big hurdle. Lots of thing go into trials for all sorts of reasons. It's getting through the trials that matters.

we'll have to see if this thing holds up. I, like many other I suspect, have my doubts this compound will survive the process.

...If it does, making metric tons will be fun for the process group.

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6. RD on April 27, 2011 10:47 AM writes...

Oh, no, no, no. How did that ever slip through the HTS filter?
I've seen strange things get into clinical trials but they usually fail and it should have been clear from the beginning that they would.
OTOH, ya' never know...

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7. milkshake on April 27, 2011 11:10 AM writes...

I think their clinical compound is originally derived from 1,3,3-trinitroazetidine (aka TNAZ), a high-performance explosive that was studied about 20 years ago as a somewhat less shock-sensitive replacement for HMX. (I doubt that TNAZ is currently used by military because it is laborious and very expensive to make, and has quite a high vapor pressure as a solid).

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8. Chemjobber on April 27, 2011 11:13 AM writes...

That's one sweet molecule.

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9. You're Pfizered on April 27, 2011 11:20 AM writes...

The patent procedure is done a 2g+ scale, so it can't be horribly dangerous to handle.

I'd love to see the pK data on this compound.

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10. MoMo on April 27, 2011 11:21 AM writes...

Good use of a bioreductive hypoxia-selective agent, although many have been studied and tried for the last 4 decades.

But why not? Cisplatin scared the best and brightest and we still use that good old German-death invention the nitrogen mustards such mechlorethamine.

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11. Industry Guy on April 27, 2011 1:04 PM writes...

You're Pfizered-

or nothing has happened....yet.....

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12. daen on April 27, 2011 1:30 PM writes...

Yeah. How hard can it be to come up with something like that, really? It's not rocket scien--

Oh ...

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13. GladToMoveToProcess on April 27, 2011 2:10 PM writes...

We were looking at other structures as radiation sensitizers, and our prep lab had the pleasure of making some tetranitro-substituted aromatics needed as intermediates. No fun, but we survived!

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14. hn on April 27, 2011 2:20 PM writes...

good way to discourage smoking

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15. wwjd on April 27, 2011 2:44 PM writes...

We really don't need anymore mustards for oncology. I hope they don't waste too many lives on that compound.

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16. Hap on April 27, 2011 3:37 PM writes...

Tagline: "Let's Blow Up Cancer"?

13: Don't polynitroaromatics like to undergo substitutions? How do you keep them intact? (At least they have pretty colors, probably).

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17. metaphysician on April 27, 2011 4:41 PM writes...

Now there's an idea: anticancer drugs that work by concentrating in the tumor cells, and then undergoing energetic decomposition. . .

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18. fred on April 27, 2011 6:15 PM writes...

The carbon/nitrogen ratio isn't that awful; how bad could it be?

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19. See Arr Oh on April 27, 2011 8:43 PM writes...

That has to be one of the coolest medchem leads ever.

@9, 13: Wonder what is was like being a member of the lead op team, wondering if your compounds would vigorously decompose at any moment...

Why not up the ante? A bis-azido, maybe an alpha-iodo amide? Where's my aziridine amide?

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20. Anonymous on April 27, 2011 8:55 PM writes...

This molecule will also vigorously react with various enzyme active site thiols. There will be odd side effects (depending on the dosage). I hope the benefits are worth the side effects!

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21. dearieme on April 28, 2011 5:44 AM writes...

"RadioRx is developing its first lead candidate..": well, I've looked at that molecule and I couldn't see the Pb atom anywhere.

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22. anonymous on April 28, 2011 6:20 AM writes...

Talk about "hot and nasty"...

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23. GladToMoveToProcess on April 28, 2011 3:24 PM writes...

Re 16: The things we made were intermediates for the med chem folks to waste, er, use. As I recall, one or two nitros were reduced, leading to various heterocycles in the targets. We handled them gently, both in the physical and chemical senses of the words. Some of the tetranitro compounds were indeed colorful!

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24. Guppy on May 1, 2011 2:40 PM writes...

Re: Metaphysician
If Happy Fun Tumor begins to smoke, get away immediately. Seek shelter and cover head. Do not taunt Happy Fun Tumor.

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25. Anonymous on May 1, 2011 3:47 PM writes...

looks like a key "reactive intermediate" to make aminothiazoles!!! Just hit it with thiourea and be done with it. Not quite sure how this company will survive...

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26. Jonadab on May 3, 2011 8:15 AM writes...

> I guess if this hits the big time,
> it'll be shipped by ground only?

If you were using it as a rocket propellant, that would be an issue, because you'd need it concentrated... For medicinal use, however, you can just dilute it with a bunch of (medically and chemically) inactive ingredients until the individual molecules of the active ingredient don't make contact with one another or anything else, and Bob is your uncle.

This stuff can hardly be more shock-sensitive than nitroglycerine (which isn't used in rocketry in pure form because it's not stable enough), and yet they put medically meaningful quantities of that veritable barrel of monkeys into pills that cardiac patients carry around routinely without so much as a cotton ball for padding. This works because the active stuff is a minority of the content of the pill, diluted with other stuff that's too stable to participate in any particularly exciting reactions.

For oncology, nobody's going to get too upset if they have to administer even as much as a few tens of grams of solution per dose, so you can dilute as much as you need to.

On the other hand...

> making metric tons will be
> fun for the process group.

Yeah, that'd be the larger issue: working with it *before* you get it all mixed and packaged and ready for distribution.

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27. GladToMoveToProcess on May 10, 2011 4:02 PM writes...

Re #7: I passed this on to an acquaintance in the high energy area. He had developed a process for TNAZ that he said was easy (but he's coming from a different world!) and high yielding; it had been run on at least 100 lb scale. The high vapor pressure is indeed the biggest problem with the stuff for military use.

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