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June 29, 2012
Odd Functionality in Drugs: A Bis-N-Oxide
Posted by Derek
There are a number of structures that I've never been quite able to make up my mind about in medicinal chemistry. One of those is the pyridine N-oxide. You really don't see those in drugs (at least, no examples come to mind), but you don't see many people trying to advance them as drugs, either. Note: the first comment points out the two key examples I'd forgotten: librium and minoxidil. Once in a while they turn up in the literature, often never to be seen again. I believe that one problem with them is that they present in a living system as mild oxidizing agents, which is the sort of thing that cells try to avoid, and I can't imagine that their pharmacokinetics are very appealing either. There are quite a few pyridine derivatives that are turned into their N-oxides on the way to being excreted, which makes you think that bringing one in from the the start is greasing the skids for fast clearance. But I've never seen one dosed, so how would I know for sure?
These thoughts are prompted by this paper from J. Med. Chem., which has an even stranger-looking benzotriazine bis-oxide. These compounds seem quite active against drug-resistant tuberculosis strains (and it's always good to see something that can kill those guys off), but I'll watch with interest to see if they can be developed into drugs. Anyone else out there ever had the nerve to push an N-oxide forward?
Comments (7)
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1. Anonymous on June 29, 2012 8:14 AM writes...
Minoxidil and librium are N-oxide drugs that have been clinically successful.
Permalink to Comment2. BioBrits SD on June 29, 2012 8:26 AM writes...
Acipimox is a Pyrazine N- oxide. I believe approved only in Europe as a niacin receptor agonist for dislypidemia
Permalink to Comment3. petros on June 29, 2012 9:23 AM writes...
In the search to develop PDE4 inhibitors it was common for companies to describe, or even develop, N-oxides of their pyridine.
Roflumilast is approved as the pyridine but the N-oxide metabolite is approximately equipotent.
Permalink to Comment4. tuky tuky on June 29, 2012 9:28 AM writes...
Per example, Minoxidil, a well-known vasodilator containing an N-oxide functionality
Permalink to Comment5. Hap on June 29, 2012 1:03 PM writes...
They look like tirapazamine analogs. SRI had the rights to the parent as a reductively activated antitumor agent and radiation sensitizer, and it was in Phase III trials (of course, that was five years ago, so I'm not thinking that went so well and, sure enough, it didn't).
Permalink to Comment6. Peter on July 2, 2012 7:17 PM writes...
Thank you for referencing my paper Derek. I am regular reader and it is nice to get noticed. I agree that N-oxides and especially Di-N-oxides are odd compounds and not typical drugs. I was also initially hesitant to pursue this series based on some of the risks mentioned. After testing the compounds in numerous assays to measure some of their in vivo properties, I have been pleasantly surprised. While it is still not a group I would intentionally add to other classes of compounds we are working on, it does impart tremendous solubility without compromising permeability.
Permalink to Comment7. Jon on July 19, 2012 12:41 AM writes...
Interesting to see these tirapazamine-like compounds being tested for TB activity. I guess the link is in the redox activation, similar to nitroimidazoles which also posses some anti-TB activity.
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