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November 23, 2009
Ozonides As Drugs: What Will They Think of Next?
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.
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 (15)
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1. You're Pfizered on November 23, 2009 10:14 AM writes...
But is it Rule of Five compliant?
;)
Permalink to Comment2. Anonymous on November 23, 2009 10:37 AM writes...
Pfizered,
Stick ye olde morpholine somewhere on there and it'll be fine.
Permalink to Comment3. 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 Comment4. 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 Comment5. 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 Comment6. 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 Comment7. 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 Comment8. 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 Comment9. 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...........
Permalink to Comment10. 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.
Permalink to Comment11. A Nonny Mouse on November 27, 2009 6:36 AM writes...
Yes, it was an ORTEP, but they were Chinese.......
Permalink to Comment12. Sili on November 27, 2009 1:11 PM writes...
I feel bad for laughing at that ...
Permalink to Comment13. 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.
Permalink to Comment14. 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.
Permalink to Comment15. 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.
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