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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: Twitter: Dereklowe

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March 5, 2008

Smaller, Wetter, Harder to Work With

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Posted by Derek

There’s an interesting article coming out in J. Med. Chem. on antibiotic compounds, which highlights something that’s pretty clear if you spend some time looking at the drugs in that area. We make a big deal (or have made one over the last ten years) about drug-like properties – all that Rule-of-Five stuff and its progeny. Well, take a look at the historically best-selling antibiotic drugs: you’ve never seen such a collection of Rule of Five violators in your life.

That’s partly because a lot of structures in that area have come from natural products, but hey, natural products are drugs, too. Erythromycin, the aminoglycosides, azithromycin, tetracycline: what a crew! But they’ve helped an untold number of people over the years. It’s true that the fluoroquinolones are much more normal-looking, but those are balanced out by weirdo one-shots like fosfomycin. I mean, look at that thing – would you ever believe that that’s a marketed drug? (And with decent bioavailability, too?)

No, you have to be broad-minded if you’re going to beat up on bacteria, and I think some broad-mindedness would do us all good in other therapeutic areas, too. I don’t mean we should ignore what we’ve learned about drug-like properties: our problem is that we tend to make allowances and exceptions on the greasy high-molecular weight end of the scale, since that’s where too many of our compounds end up. It wouldn’t hurt to push things on the other end, because I think that you have a better chance of getting away with too much polarity than you have of getting away with too little.

One reason for that might be that there are a lot of transporter proteins in vivo that are used to dealing with such groups. It’s easy to forget, but a great number of proteins are decorated with carbohydrate residues, and they’re on there for a lot of reasons. And a lot of extremely important small molecules in biochemistry are polar as well – right off the top of my head, I don’t know what the logD or polar surface area of things like ATP or NAD are, but I’ll bet that they’re far off the usual run of drugs. Admittedly, those aren’t going to reach good blood levels if you dose them orally; we’re trying to do something that’s rather unnatural as far as the body’s concerned. But we could still usefully take advantage of some of the transport and handling systems for such molecules.

But that’s not always easy to do. We all talk about making our compounds more polar and more soluble, but we balk at some of the things that will do that for us. Sure, you can slap a couple of methoxyethoxys on your ugly flat molecule, or hang a morpholine off the end of a chain to drag things into the water layer. But slap five or six hydroxyls on your molecule, and you’ll be lucky not to have the security guards show up at your desk.

There are, to be sure, some good reasons why they might. Hydroxyls and such tend to introduce chiral centers, which can make your synthesis difficult and dramatically increase the amount of work needed to fill out the structural possibilities of your lead series. That’s why these things tend to be (or derive from) natural products. Some bacterium or fungus has done most of the heavy lifting already, both in terms of working out the most active isomers and in synthesizing them for you. Erythromycin’s a fine starting material when you can get it by fermentation, but no one would ever, ever consider it if it had to be made by pure total synthesis.

There’s another consideration, which gets you right at the bench level. For an organic chemist, working with charged, water-soluble compounds is no fun. A lot of our lab infrastructure is built for things that would rather dissolve in ethyl acetate than water. A constant run of things with low logD values would mean that we’d all have to learn some new skills (and that we’d all probably have to spend a lot of time on the lyophilizer). Ion-exchange resins, gel chromatography, desalting columns – you might as well be a biochemist if you’re going to work with that stuff. But in the end, perhaps we might be better off, at least part of the time, if we were.

Comments (13) + TrackBacks (0) | Category: Drug Industry History | In Silico | Infectious Diseases


1. Anon on March 5, 2008 10:35 AM writes...

How about mupirocin and retapamulin as other examples of wacky antibiotics. Retapamulin was only recently launched.

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2. milkshake on March 5, 2008 11:12 AM writes...

The reason why so many antibiotics are "ugly" by medchem standards and stil work great in vivo is that 1) they were selected by nature (which has its way of doing things in redundand complicated fashion) 2) antibiotics do not have to be human-cell permeable. If antibiotics were tested in human cell culture, I think many of them would fail. Also, some of these compounds have fantastic target affinity which helps to compensate for their less than awesome drug-like properties. In fact there is plenty of room for for improving on nature as semisynthetic lactam and erythromycine antibiotics show.

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3. Anonymous on March 5, 2008 11:55 AM writes...

You forgot nucleoside based anti-virals/anti-cancer compounds which typically have lots of hydroxyls and also tend to be low molecular weight and very polar in nature

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4. DLIB on March 5, 2008 12:01 PM writes...

Hear Hear...

Now only if there was a method whereby you could learn about these types of binding modalities earlier and ealier so that the leads you get are amenable.

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5. sroy on March 5, 2008 1:27 PM writes...

One of the original driving force behind the 'Lipiniski Rule of 5' was to find a quick way to identify compounds with good 'passive' oral biovailability and good 'passive' cell permeability.

Both oral bioavailability and cell permeability depend on the membrane residency time of a given drug. High passive transport can be achieved with a reasonably greasy compound. Too water soluble = poor membrane residency, high lipid solubility = formulation issues and drug does not leave membrane easily.

However since the cell membrane has more than lipids - pharmacophores or functionalizations that allow drugs to bind to membrane localized proteins can improve the absorption of compounds that could not otherwise pass through a lipid membrane. Look at bacterial, fungal and plant derived toxins - many have moeities/ functionalizations that are absolutely necessary to get into a cell.

With anti-microbials, it is not just evolution, but the route of delivery of many antimicrobials - parental. Therefore oral bioavailability is a often a moot issue. Compliance remans high because many infections have significant acute morbidity and motality and treatment is often acute or subacute. TB, HIV, HBV, HCV are pretty much the only major microbial diseases that require drug treatment for more than 8 weeks. It also helps that some drugs resemble the natural substrates of their targets and can ride the same 'elevators'- esp nucleoside/ nucleotide based drugs.

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6. Walt on March 5, 2008 3:49 PM writes...

One class of antibiotics that you did not mention, Derek, is the first antibiotic, sulfanilamide. It is pretty small and wet on today's standards. And it had to be small to be transported into the cell to muck up bacterial folate metabolism. Incidentally, there is a great book --Demons under the microscope -- which tells the story of "sulfa" which is essentially the story of medicinal chemistry and how it began right at the German version of the "Wonder Factory" back when Bayer was part of the infamous I.G. Farben.

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7. sroy on March 5, 2008 4:38 PM writes...

The contribution of research on sulfonamides in the development of modern medicinal chemistry is one of the most important historical lessons in drug development.

Sulfonamides not only gave us the first broad spectrum antibacterials, but research on the side-effects of analogues gave us carbonic anydhrase inhibitors, thiazide diuretics, anti-diabetic sulfonylureas, sulfasalazine -first treatment for ulcerative colitis. If you think about it, it represents a very good paradigm for drug development namely identify a reasonably safe and synthetically accessible scaffold (privileged scaffold) with some therapeutic activity, develop well observed side effects of analogues and refine compounds.

The only other comparable story is the identification of the H1 antagonist pharmacophore that has given us not just antihistamines, but the first antidepressants (tricyclics), the first synthetic anti-emetics (more dopamine blocking than anticholinergic -prochlorperazine) the first anti-psychotics (chlorpromazine). Even the first SSRIs are developments of the antihistamine scaffold (diphenhydramine and chlorpheniramine scaffolds).

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8. ananymous on March 5, 2008 5:13 PM writes...

"But slap five or six hydroxyls on your molecule, and you’ll be lucky not to have the security guards show up at your desk""

Could Derek or some one explain this in a bit more detail? Lately I was thinking to add couple of extra hydroxyls to a drug (natural product drived) to stop it from crossing the BB, and thus circumvent the neurotoxic effects. But now that I hear this, I wanted to be sure as to what else could it cause?

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9. MikeEast on March 5, 2008 5:43 PM writes...

#8 - I think Derek is implying it can cause unemployment!

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10. milkshake on March 5, 2008 8:53 PM writes...

if you want to mess up the CNS permeability than even a better choice is carboxyl: look at Zyrtec and Allegra. Sulfonamides are also reliable for making things brain-non-penetrable.

(Right now I have an exactly opposite problem, making things greasy and basic so that they get into brain)

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11. Kay on March 6, 2008 11:14 AM writes...

What happens when people begin to ignore The Rules? Chaos, I tell you.

Mind The Rules, for they have been good for us.

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12. GATC on March 7, 2008 9:57 AM writes...


Glad to see that you have revisited the antibacterial space. Here are a few points worth pondering:

1)When considering the chemical diversity of natural antibiotic molecules, don't forget to contrast that to the complexity of the antibacterial target space. I think this is often overlooked by medchems (ribosome, cell wall/membrane, DNA/RNA replication, general metabolic inhibitors). Much like cramming all of the available human cell targets into one unicellular organism.I still have to laugh when I hear talks mentioning the "basic antibacterial pharmacophore". Also, one has to wonder why nature seemed to overly select for molecules that hit the ribosome.

2) Don't count out host-cell penetration since many bacterial pathogens have "intracellular" life styles during actual infections. This too is often overlooked.

3) I am amazed at all of the hay that is made about protein binding. As a rainy-day exercise, check out the range of protein binding relative to clinical efficacy for the current crop of antibacterials.

4) Considering the advent of modern antimicrobial chemotherapy, Domagk's prontosil (the very first sulfa drug) had no in vitro antibacterial activity (MIC). It was only active after metabolic activation in the host. What an interesting story; not only the first sulfa drug but most likely the first case of a "pro-drug". For one of the better historical accounts of this story as well as many of the other early antibiotics, see Frank Ryan's "The Forgotten Plague: How the Battle Against Tuberculosis Was Won - And Lost".

5) Regarding mupirocin and retapamulin (and the topical antibiotics in general), did these two show any real superiority when compared to triple-antibiotic ointment? Or were they ever compared to triple-A? I could never understand exactly why GSK bothered with these unless they failed systemic criteria and they thought they could recover some of the R&D investment with a topical formulation.

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13. Haberlfl on August 29, 2008 5:37 AM writes...

Another article worth to read in this context is:

F. von Nussbaum, M. Brands, B. Hinzen, S. Weigand, and D. Habich. Antibacterial natural products in medicinal chemistry–exodus or revival. Angew. Chem. Int. Ed. Engl., 45(31):5072–5129, 2006.

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