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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 8, 2010

Not Gonna Make That One

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Posted by Derek

A discussion at work the other day got me to thinking: what structures do you medicinal chemists out there just refuse to work on? Any? We all have our own prejudices - in fact, if you get enough chemists into one conference room, one or another of them will probably rule out just about any structure you propose. Try that sometime, and be sure to sneak a few marketed drugs in there to tick people off. Don't like organoazides? Michael acceptors? Nitroaromatics? Epoxides? Chloromethyl ketones? They're out there working in the real world and making real money.

Now, I'm not saying that you should concentrate on these things. The success rate for (say) chloromethyl ketones is surely lower than for a lot of other compound classes, and there's only so much time and money available. That's why I have personal rules like "No Naphthyls". If someone shows me a structure with a raw naphthalene hanging off it that works, well, good for them, and I guess I'd work on it on that basis. But I won't contribute any myself, because I think the odds are too low.

But I have even more deep-seated prejudices. There are some structures that I just don't think have a chance, even if it looks like they work at first. I'd rather kill them immediately than take the (grave) chance of wasting everyone's time. The first thing I can think of on such a list would be quinones and their ilk. There are just too many other bad things that they're capable of. Now that I've said this, I feel sure that someone is come up in the comments with an example of a quinone that's making five hundred million dollars a year or something. But I sure can't think of one myself, and I just don't see the point of trying to make a drug out of such a structure (unless their lively reactivity is part of some nasty mechanism all its own, in which case, good luck to you).

So call me close-minded. But no quinones.

Comments (21) + TrackBacks (0) | Category: Life in the Drug Labs


1. Ed on March 8, 2010 9:13 AM writes...

For me, anything with a 2-naphthylamine unit goes straight into the discard pile - too many issues with carcinogenic metabolites for my liking.

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2. Ortep on March 8, 2010 9:27 AM writes...

Anything that looks like it belongs in a paint. White or yellow, stay mellow. Red, purple or brown, flush it down.

Thiophenes make me cringe as well.

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3. petros on March 8, 2010 9:27 AM writes...

While I can think of some approved quinones, eg Takeda's seratrodast, a TP receptor antagonist, they haven't generated much money.

But the same isn't true of napthyl containing compounds eg naproxen

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4. jf on March 8, 2010 9:27 AM writes...

Adriamycin and Mitomycin have been around for a long time. I certainly wouldn't want to take them but they have made a lot of money (esp. Dox) and have saved more lives than Viagra and Chantix combined.

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5. A Nonny Mouse on March 8, 2010 9:53 AM writes...

Atavaquone for malaria, which is now coming in as a generic.

There is also a related compound,Buparvaquone,which is used in African cattle for parasitic diseases.

Both based on a series of compounds originally made by Louis Fieser.

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6. chucky on March 8, 2010 10:15 AM writes...

Duloxetine (Cymbalta), the antidepressant from LLY sells at least a couple of billion and has both a thiophene and a napthalene, maybe they cancel each other out :)

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7. DLIB on March 8, 2010 10:48 AM writes...

Remember the study where 13 med chemists were shown lists of compounds....I think 22,000 in all --- only one was agreed upon by all as a bad actor. This is a serious problem industry. What type of data would be required in addition to pure structure to get unanimity amongst med chemists??? MOA?? Calorimetry???

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8. Hap on March 8, 2010 10:58 AM writes...

The mitomycins are supposed to be some of the most toxic of the anticancer drugs (and that's saying something) - taking them's better than dying, but not exactly what one would choose. Also, they're either natural products or pretty closely derived from them - it's not like someone said, "Hmmm - let's make some quinones today..."

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9. milkshake on March 8, 2010 11:01 AM writes...

Doxorubicin and Mitoxantrone are anthraquinones - and a mainstay of chemotherapy - intercalators and TopoII inhibitors. Nasty indeed.

The Michael-acceptor properties of Sutent are vastly overstated. Everyone who sees it the first time will point the C=C as a problem source (and it is - the molecule is light sensitive because it is so incredibly yellow and sunlight causes reversible cis/trans photoisomerization in solution) but the C=C reactivity towards nucleophiles is poor. You can reduce C=C if you reflux it with borohydride but even non-hindered amines do not like to add to it (they eliminate right back) and glutathione additon also was never a problem. It makes sense when you realize how electron rich the pyrole substituent is, and the addition to C=C ruins the extensive conjugation and the H-bonding of pyrrole NM to oxindole O.

There are innocuous natural substances like curcumin that look even scarier than Sutent.

Working on ugly compounds: we once started with isatin acylhydrazone "lead" - which is as ugly as it gets - and reworked it into a sensible heterocycle which also happened to be a new low-molecular weight c-Met kinase scaffold , but it took lot of work and good crystalography. So yes, one does not want to start working on ugly molecules because scaffold changes are hard.

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10. LeeH on March 8, 2010 11:15 AM writes...


I agree with your philosophy on avoiding certain substructures, but not necessarily ruling them out.

A given substructure has a certain probability of having adverse properties associated with it. Once that probability reaches some level (let's say, 10%?), you might want to avoid it unless there's some very compelling reason not to do so (like you've run out of options). And even then, you'd better be careful to monitor the liability in question rather closely.

In the end, the exception doesn't prove the rule. By the same token, those that ignore history are doomed to repeat it.

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11. Cloud on March 8, 2010 12:18 PM writes...

DLIB- I am not a medicinal chemist, but I suspect the answer to your question is "a complete and unambiguous understanding of how chemicals are metabolized and also of how they (and their metabolites) will act in the various tissues of the body."

Which translates to: don't hold your breath.

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12. Curryworks on March 8, 2010 2:01 PM writes...

So for the organic azides do impurities from a "click" reaction have medicinal potentail?

How does the community feel about the "click" reaction for medchem?

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13. Cellbio on March 8, 2010 2:15 PM writes...

Awe shucks, just make antibodies, no problems there, just spend the 50 million to get to the clinic and it is all smooth sailing...oops

Infections and deaths force Biogen, Roche to suspend blockbuster program
March 8, 2010 — 8:10am ET | By John Carroll
In a significant setback, Biogen Idec and Roche have suspended the troubled development program of ocrelizumab for rheumatoid arthritis, and analysts are already questioning if work related to multiple sclerosis may soon follow.
The companies made their move after an independent safety board said that the risks outweighed the potential benefit from the experimental therapy, noting that serious and opportunistic infections had afflicted patients taking the therapy, some of whom died. Safety concerns had already forced researchers to halt two clinical trials for rheumatoid arthritis and lupus.

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14. hugues on March 8, 2010 2:15 PM writes...

what about diazoketones ?!

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15. Handles on March 8, 2010 3:47 PM writes...

Re: diazoketones/azides/click triazoles

The problem with these is scale-up. Most manufacturers will refuse to quote on safety grounds, then the few that are equipped to deal with explosion hazards will charge you an arm and a leg for GMP manufacture. No matter how good the compound looks, theres probably a better way to get the same activity.

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16. Pete on March 9, 2010 12:06 AM writes...

I am always wary of anilines because of potential for Ames activity as well as reactivity (e.g. formation of quinoid electrophiles). In a therapy area like diabetes or obesity where the compound has to be squeaky clean, I'd also be worrying about anilides. In molecular recognition terms, the anilino amino group is usually an unexceptional donor and acceptor of hydrogen bonds and it can be argued that there is a good chance that it can be replaced. Anilines are encountered in sulfonamide drugs.

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17. milkshake on March 9, 2010 12:42 AM writes...

anilines are mostly OK as long as they hang from an electron deficient ring - i.e. aminopyridines, aminobenzoic acids. Its the metabolic activation that makes the trouble, N-aryl-hydroxylamines and quinoid oxidation products are the actual nasties

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18. Pete on March 9, 2010 5:59 PM writes...

I wouldn't call an aminopyridine an aniline but suspect that there will be instances of amino heterocycles showing Ames activity even when the heterocycle is electron-withdrawing. Carboxylic acids usually deprotonated under normal physiological conditions and I'd be interested to know how electron withdrawing the carboxylate anion is. A dimethyl aniline is likely to be a very different beast to the unmethylated parent.

If you are planning to move an aniline (unmodified amino) forward you are going to have to show that it is Ames-clean and I'd suspect there will pharmacokinetic (as opposed to safety) issues as well. My main point is that an anilino amino group is typically an unimpressive molecular recognition element and rarely an essential feature for binding so why bother to carrry all its baggage. Similar arguments can be made against nitro groups and I'll be discussing in the FBDD Literature blog in a post or two's time.

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19. glinkst on March 13, 2010 1:27 AM writes...

How about Buckyballs? I don't think any of them are in drugs so they must be extremely dangerous.

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20. Morten G on March 15, 2010 4:43 PM writes...

Vitamin K! And it doesn't even have a tox dose.

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21. TC KING on March 31, 2010 12:51 PM writes...

Great blog going here for those med chemists who seek the truth. There is som much BS in drug design at the pharma level and Ego stroking that its a miracle anything gets done and any new drugs exist. So I really appreciate this site!

Throw out the reds? You would have missed doxorubicin. Nitro groups? metronidazole, and the list goes on and on. Diquinones? FAGIT ABOUT IT.

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