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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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November 23, 2009

Ozonides As Drugs: What Will They Think of Next?

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Posted by Derek

You know, I often think that I have too narrow a view of what kinds of structures can go into drug molecules. (That may come as worrisome statement for some past and present colleagues of mine, who feel that my tolerances are already set a bit too wide!) But I do have limits; there are some structures that I just wouldn't make on purpose, and which I wouldn't submit for testing even if I made them by accident.

Surely ozonides fall into this category. But when I put the "Things I Won't Work With" stamp on them, at least as far as making them on scale and actually isolating them, some readers pointed out that people were investigating them for antimalarial activity. And here we are, with a new paper in J. Med. Chem. on their activity and properties.

Arterolane is the lead compound, which is in Phase III trials as a combination therapy. And it has to be one of the funkier structures ever to make it as far as Phase III, for sure, with both an ozonide and an adamantane in it. Those two, in fact, sort of cancel each other out - the steric hindrance of the adamantane is surely one of the things that makes the ozonide decide not to explode, as its smaller and more footloose chemical relatives would. You get blood levels of the stuff after oral dosing, a useful (although not especially long) half-life, and no show-stopping toxicity.
arterolane.jpg
Endoperoxides are already known as antimalarials, thanks to the natural product arteminisin, which has led to two synthetic derivatives used as antimalarials. So the step to ozonides was, structurally, a small one, but must have been rather larger psychologically. And that's definitely not something to discount. I probably wouldn't have made compounds of this sort, and it's unnerving (even to me) that arterolane has gone further into the clinic than anything I've ever made. I have to congratulate the people who had the imagination to pursue these things.

Comments (18) + TrackBacks (0) | Category: Drug Development | Infectious Diseases | Odd Elements in Drugs


COMMENTS

1. You're Pfizered on November 23, 2009 10:14 AM writes...

But is it Rule of Five compliant?

;)

Permalink to Comment

2. Anonymous on November 23, 2009 10:37 AM writes...

Pfizered,

Stick ye olde morpholine somewhere on there and it'll be fine.

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3. petros on November 23, 2009 10:47 AM writes...

And its stability in tropical climes is?

Any antimalarial has to be very chemically stable becuase of the extreme conditions it is likley to be stored in

Permalink to Comment

4. You're Pfizered on November 23, 2009 11:08 AM writes...

If it's in Phase III, all kinds of stress-tests for stability have been done by the corresponding development areas, giving a read on what conditions the drug product needs to be stored under and what the shelf-life under those conditions would be.

Had there been any type of severe thermal or chemical instability, it should have been discovered by now and its development probably would have ended.

Permalink to Comment

5. Little Miss Process on November 23, 2009 11:47 AM writes...

Under the right structural circumstances, ozonides can be quite stable. I made one during my postdoc, and it didn't go "bang", although it did rapidly rearrange to the product I wanted with a little acid. As Pfizered says, the process safety guys will have tested it for thermal stability, and at this phase, the formulation groups will have acquired degradation data too. Well, I say "will have". I don't work for the company in question, so perhaps I should say "should have".

Permalink to Comment

6. Petros on November 23, 2009 12:11 PM writes...

This link gives some details of the studies done

http://www.mmv.org/IMG/pdf/02_RBX11160_-_Ranbaxy_-_MMV_conference_Mumbai_IRS.pdf

Permalink to Comment

7. Sili on November 23, 2009 3:21 PM writes...

Wouldn't a qualified guess be that they were shooting for a peroxide, and this happened to pop out instead?

Permalink to Comment

8. Igor on November 23, 2009 6:14 PM writes...

With many successful drugs out there that look "ugly", e.g. metformin and taxol, from a typical small molecule perspective, this one really doesn't look all that unusual. After having some difficulty in decomposing some hindered ozonides in the past, the stability of this one does not surprise me.

As a generalization, I do think that we as med chemists need to try to step out of the heteroaryl-core-attached-to-some-lipophilic-groups-and-a-solubilizing-group mentality; otherwise, we might as well move overseas and just make analogs.

I hope the ozonide works and actually is a benefit to society, regardless of its perceived structural liabilities.

Permalink to Comment

9. A Nonny Mouse on November 24, 2009 12:59 PM writes...

I remember being shown a paper by a colleague in the mid-1980s. He had been sent the paper to review which was the X-ray structure of a natural product with anti-malarial properties. He showed it to me and I said "NO WAY!". We decided that they had definitely done something wrong and got carbons and oxygens mixed up as the structure could not possibly exist. Yes, it was Artemesin...........

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10. Sili on November 25, 2009 11:41 AM writes...

I take it it wasn't an Ortep drawing, A Nonny?

More than once have I shook my head at published work (even by people I know), where they've obviously swapped around Nitrogen and Carbon in an uncoördinated pyridyl ring.

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11. A Nonny Mouse on November 27, 2009 6:36 AM writes...

Yes, it was an ORTEP, but they were Chinese.......

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12. Sili on November 27, 2009 1:11 PM writes...

I feel bad for laughing at that ...

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13. Artem on November 28, 2009 9:04 PM writes...

Given the fact that nitroglycerin is a drug since eighteen-freakin-seventy - this one doesn't shock me at all.

I've had my share of failed attempts to persuade the wise and powerful chemists to make small molecules that are 'obviously wrong for numerous/obvious reasons I am too busy to go into' - only to watch those very same things appear in a more cavalier company's patent literature years later. To me the lesson of the story is - get out of the box or be buried in it.

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14. Design Monkey on November 30, 2009 11:25 AM writes...

Not about ozonides, but another odd element - actually there is a silicone containing drug, that is being sold for human use and with (quite) a bit funky structure even - 1-(chloromethyl)silatrane, mival, as a baldness treatment agent in Russia. Most papers and information about it are available in russian only.

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15. petros on December 1, 2009 3:44 PM writes...

Another ugly drug, containg selenium, is ebselen
http://en.wikipedia.org/wiki/Ebselen.

This was filed, but not approved, in Japan.

Permalink to Comment

16. tanygeo on June 15, 2010 10:34 PM writes...

The initiative taken for the concern is very serious and need an attention of every one. This is the concern which exists in the society and needs to be eliminated from the society as soon as possible. The people are loosing their moral while becoming modern. The society needs to be attentive that moral value.
=========================================
Best Pharmacy Drugs

Permalink to Comment

17. Relevant on May 3, 2012 2:01 AM writes...

This discovery was driven by a new synthetic reaction discovered by Karl Griesbaum of Karlsruhe University in Germany, said Vennerstrom. "We realized that his technology could enable us to synthesize some very interesting compounds, and this particular peroxide is stable enough that we can do some very interesting chemistry on it. In that way it's quite similar to artemisinin."

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18. Ross Herman on September 17, 2012 7:33 PM writes...

Typical "scientist" all decisions are based on your emotional response to the shape of the Lewis structure, like you have some insight as to what molecular shapes will be acceptable medications. You are probably taking your cholesterol medication and getting your yearly flu shot?

Permalink to Comment

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