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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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March 25, 2009

Two! Two! Two Drugs in One!

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Posted by Derek

There's an idea that shows up in the antibiotic field that seems a bit crazy by the standards of other therapeutic areas. Since bacteria develop resistance to single agents, why not take two different classes of antibiotic molecule and, y'know, string 'em together somehow? How about that, eh?

Well, it's the sort of thought that occurs either to people who don't know much about drug discovery, or to those who know an awful lot. In between, you're probably going to dismiss that one as something of an eye-roller. But while it's got some problems, it's not quite as much of a bozo move as it appears. Here's an example that just showed up in J. Med. Chem., where a group tied Cipro (ciprofloxacin) to neomycin.

The first objection is "Why don't you just give people two pills, instead of trying to make them all into one molecule?" (Here's a review that talks about both options). Well, one answer is that two different agents are going to have different absorption and PK, whereas a conjugate drug will be coming on all at the same time, which could be an advantage. But a more compelling answer is that the new conjugate is going to be a different creature at both of its drug targets, and might well be different enough at both to qualify as a new agent to the resistant strains.

The molecules described in that paper above are, depending on your point of view, fluoroquinolones with a lot of sugars hanging off of them - most unusual as far as traditional quinolone SAR - or neomycin oligosaccharides with some odd heterocycles hanging off of them in turn, which is also not the sort of thing that's usually tried on that scaffold. So if you can still hit both targets, you may well be able to hit them with something they haven't seen before (and may not yet know how to deal with). Importantly, in the case of those quinolone/neomycin thingies, some evidence is shown in the paper that bacteria have a harder time developing resistance to the new compounds. (In order to completely evade them, the bacteria will have to mutate out of both targets, too, but that advantage mostly holds with two separate pills as well).

But all this brings up the second objection: how do you think you're going to get away with hanging all that stuff off an active compound? Well, that's why this trick is usually done with known antibiotics. The SAR of these things has been well worked out by now, and that includes the parts of the molecule that don't seem to have much effect on things. Those will be the preferred positions to attach your linking groups, they're the nonessential region(s) of the molecule that can be messed with.

There's a potential show-stopper in all this, though, and it can be seen on display in the J. Med. Chem. paper. Sticking two drug molecules together, no matter how you do it, is going to make a rather large entity. Neomycin, for its part, didn't start out very small, and the linkers used in this paper aren't the tiniest things on the shelf, either (although I do like the use of the triazole click reaction, mentioned yesterday as well). It turns out that the resulting double-barreled compounds are better than plain neomycin, but worse than plain Cipro. And this happens in spite of the fact that when you assay them against the fluorquinolone target enzymes (DNA gyrase and topoisomerase IV), the new compounds are actually more potent than the original drug. So what's the problem?

Well, the problem, almost certainly, is that these things are probably just too huge. The disconnect between enzyme and bacterial potency here may well reflect trouble getting into the bacteria (although that doesn't seem to be hurting the neomycin end of the activity so much). Larger molecules are trouble when dosed orally, too, and I'd expect compounds like the ones shown to be difficult to develop as traditional pills. (That said, there's a real need for IV-based antibiotics for nasty hospital-derived infections, so something like this could still fly, as long as it showed activity against real bacteria).

So this idea is hard to realize, but it's not necessarily crazy. It keeps showing up in the antibiotic world, and here's an account of the same concept being applied to malaria therapy. Eventually someone's going to get this to work.

Comments (19) + TrackBacks (0) | Category: Drug Development | Infectious Diseases


COMMENTS

1. Ty on March 25, 2009 8:12 AM writes...

Curis, Inc. is developing a dual kinase/HDAC inhibitor (Phase 1; WO 2008033747); a Tarceva/Iressa-like quinazoline core with a long side chain containing a hydroxamic acid (think SAHA).

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2. Harry on March 25, 2009 8:32 AM writes...

Oldest two-antibiotics in one pill I know of off-hand is Bactrim (sulfamethoxzole + trimethoprim).

Still pretty effective after Lord kows how many years.

Pretty good idea, but the execution sounds pretty difficult.

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3. Anonymous on March 25, 2009 8:32 AM writes...

How about coming up with a hybrid of two structures (not linking) i.e combine the active pharmacophores of the two drugs that would inhibit two different enzymes? Is there any drug of that sort currently approved? or any references where in it is tried? Essentially dual targetting approach with single molecule.

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4. Anonymous on March 25, 2009 8:42 AM writes...

I did not notice Ty's comment:

Curis, Inc's dual kinase/HDAC inhibitor (Phase 1; WO 2008033747)development is pretty interesting. Probably, this approach should take care of some of those issues pointed, rightly so, by Derek.

What is your take on this approach, Derek?

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5. Erock on March 25, 2009 9:02 AM writes...

As a hospital pharmacist I could definitely see the benefit for IV antibiotics here. Especially if two synergistic AB's could be fused in the same compound (i.e., a beta-lactam like ampicillin or meropenem with and aminoglycoside like gent). It would be nice to have a compound like this in our back pocket in case we start to see an increase in resistant bacteria.

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6. Tim on March 25, 2009 9:12 AM writes...

I still think there is merit conjugating antibiotics to efflux pump inhibitors. This ACS Chemical Biology paper is an effective use of such an approach.

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7. anon the II on March 25, 2009 9:14 AM writes...

I think the answer to #3 is that there are lots of examples. It's called a lack of selectivity. There are a few on the market, which marketing departments call dual inhibitors. In the computer world, they laugh and say "It's a feature, not a bug".

This linking thing is really not a great idea. It would be rare that you had two drugs with the same potency. Of course, it might be worth trying but I think there are better ways to spend the money.

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8. 2cents on March 25, 2009 9:29 AM writes...

Combining two molecules covalently is a crappy idea which has been beat to death in the antibiotic field. These folks did it with click chemistry - which seems to be the only piece of novelty if you can call it that.

As far as I know nothing has come out of this idea except some trivial publications. I worked on antibacterials some time ago. We were trying the "screen novel scaffold against bacteria" approach and had some modest success. We had good to decent activity in cell culture but the activity went away when tested in the presence of serum. This is a big problem especially with more greasy scaffolds and if you dont have activity in the presence of serum, you might as well just quit. We tried increasing the polarity of the molecules but that killed our activity. Although what seemed to work every time for activity was appending halogens (especially chlorine) onto the scaffolds. It seemed to help the compounds get past the bacterial cell membranes.

A beautiful example of developing an antibiotic that is not natural product derived is the Linezolid story. Linezolid is not the most potent compound out there but it has awesome physico-chemical properties, excellent bioavailability and it does not loose activity in the presence of serum. Some really nice work by the Pharmacia team after they licensed the scaffold from Dupont.

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9. CMC Guy on March 25, 2009 9:42 AM writes...

This seems to be of those "good research concepts" that cycles through varied interest levels periodically. I have seen/heard about such projects several times (in both antibiotics and Cancer drugs) but then the execution has never been fully realized that I am aware of. Most of these things bring "nightmares" to process chemists and formulators, who have enough headaches thank you. Although per normal if something so good is discovered the development issues will likely be secondary to getting the project done.

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10. ithink ithink on March 25, 2009 10:45 AM writes...

Lilly's Zyprexa-Prozac combo wins expanded use

http://www.reuters.com/article/rbssHealthcareNews/idUSN2316881220090323

Permalink to Comment

11. Dan on March 25, 2009 11:06 AM writes...

Not so surprising about the neomycin component retaining activity. In addition to inhibiting the 30S ribosomal subunit, aminoglycoside antibiotics also displace cations from the bacterial surface. Cations link LPS in gram-negative bacteria. This creates holes in the cell surface and may be a primary cause of cidal activity via lysis.

Permalink to Comment

12. anon on March 25, 2009 1:36 PM writes...

I'm surprised no one has mentioned Theravance.

They've got 2 programs that have successfully completed Phase 2 trials that have dual functionality. One is an IV antibiotic linking a cephelosporin and a vancomycin (J. Antibiotics, doi:10.1038/ja.2008.80 ). The other program is a Muscarinic Antagonist-Beta2 Agonist.

Note that neither of these programs are oral dosing, so molecular size is less of an issue.

Permalink to Comment

13. JC on March 25, 2009 2:25 PM writes...

So then why the bloodbath last year at Theravance?

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14. Chrispy on March 25, 2009 2:31 PM writes...

Perhaps y'all saw the Two-in-one Designer Antibodies article out of G'tech in the latest Science. Through phage display, crystallography, scanning mutagenesis (and pounding) they managed to derive an antibody which binds both VEGF and HER2. It really isn't clear what practical utility this has but it is interesting that it can be done.

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15. anon on March 25, 2009 3:05 PM writes...

JC - They had FDA delays w/ their lead antibiotic Televancin.

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16. Anonymous on March 25, 2009 5:55 PM writes...

#3 said: "How about coming up with a hybrid of two structures (not linking) i.e combine the active pharmacophores of the two drugs that would inhibit two different enzymes?"

I think that lots of people have tried that sort of thing, but it is really hard. SAR usually doesn't track between the two. As you optimize potency for one enzyme you often lose potency at the other enzyme.

Permalink to Comment

17. Tim on March 25, 2009 10:06 PM writes...

This seems like the logical extension of some work that Sharpless & Co. published a few years ago (http://pubs.acs.org/doi/abs/10.1021/ja043031t). If click chemistry can be used to screen for allosteric inhibitors based on their interactions with a known active site inhibitor, it makes sense that the same methods could be used to combine two existing drugs and increase their potency. I don't know how much of an impact the Sharpless/Kolb paper had--I defected to law school shortly after it was published, so my journal reading has plummeted. It might be interesting to find out though.

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18. Anonymous on March 26, 2009 4:52 AM writes...

Derek,

Look in the 90's at work from Roche and Procter and Gamble. They hooked together betalactams and quinolones. The thought was that if the lactam opened, the quinolone would be available in its naked state to work on the DNA gyrase. Roche had compounds in the clinic from this work.

Permalink to Comment

19. anon on March 27, 2009 10:00 AM writes...

> Since bacteria develop resistance to single agents

No, they don't; some already have it otherwise none would have survived. I thought we gave up Lamarckianism long ago.

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