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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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June 15, 2009

Ugliness Defined

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Posted by Derek

Yesterday's post on so-called "ugly" molecules seems to have touched a few nerves. Perhaps I should explain my terms, since ugliness is surely in the eye of the beholder. I'm not talking about particular functional groups as much as I'm talking about the whole package.

First off, a molecule that does what it's supposed to do in vivo is (by my definition) not truly ugly. The whole point of our job as medicinal chemists is to make active compounds - preferably with only the activity that we want - and if that's been accomplished there can be no arguing. Of course, "accomplished" has different meanings at different stages of development. Very roughly, the mileposts (for those of us in discovery research) are:

1. Hitting the target in vitro.
2. Showing selectivity in vitro.
3. Showing blood levels in vivo.
4. Showing activity in vivo.
5. No tox liabilities in vivo.

And these all have their gradations. My point is that if you've made it through these, at least to a reasonable extent, your molecule has already distinguished itself from the herd. The problem is that a lot of structures will fly through the first couple of levels (the in vitro ones), but have properties that will make it much harder for them to get the rest of the way. High molecular weight, notable lack of polarity (high logP), and notable lack of solubility are three of the most important warning signs, and those are what (to me) make an ugly molecule, not some particular functional group.

My belief is that, other things being equal, you should guard against making things that have trouble in these areas. You may well find yourself being forced (by the trends of your project) into one or more of them; that happens all the time, unfortunately. But you shouldn't go there if you don't have to. It's also true that there are molecules that have made it all the way through, that are out there on the market and still have these liabilities. But that shouldn't be taken as a sign that you should go the same route.

Ars longa, vita brevis. There's only so much time and so much money for a given project, and your time is best spent working in the space that has the best chance of delivering a drug. A 650 molecular weight compound with five trifluoromethyl groups is not inhabiting that space. It's not impossible that such a compound will make it, but I think we can all agree that its chances are lower compared to something smaller and less greasy. If the only thing you can get to work is a whopper like that, well, good luck to all concerned. But we have to depend on luck too much already in this business, and there's no reason to bring in more.

Comments (13) + TrackBacks (0) | Category: Drug Development | Life in the Drug Labs | Pharmacokinetics


1. Chemjobber on June 16, 2009 7:42 AM writes...

A 650 molecular weight compound with five trifluoromethyl groups is not inhabiting that space.

Torcetrapib wasn't that far off and it *almost* made it. Except it didn't.

Question: did it represent foolhardiness or risk-taking on the part of PFE?

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2. Derek Lowe on June 16, 2009 8:07 AM writes...

I think that torcetrapib is an example of being forced into a particular chemical space. CETP has such greasy binding sites that most things that hit it well are going to be unappealing. I think that anyone trying to develop a compound like that knows (or should know) that they're running a real risk, which they may decide is worth it considering the size of the potential market.

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3. Chemjobber on June 16, 2009 9:05 AM writes...

Considering the efforts made into formulating the stuff, I think they knew and took the risk. Too bad that it didn't pay off.

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4. Cellbio on June 16, 2009 2:55 PM writes...

A little off topic, but my favorite ugliness is a profile offered by inexperienced small companies that is a variation of Derek's list:

Compound 1 hits the target in vitro but is nonspecific
Compound 2 is weak, but appears to be specific (target inhibition occurs near solubility limit?)
Compound 3 has reasonable PK, but no potency or selectivity, but us well tolerated (meaning the mice stayed on their feet)
In vivo efficacy can be noted with 100 mg/kg, TID dosing of compound 1, with only a few animals dropping.

What? You want all the desirable properties in one molecule? Oh, well that will only take a few dollars more....

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5. dez on June 16, 2009 3:17 PM writes...

What are the thoughts on anilines?

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6. milkshake on June 16, 2009 3:39 PM writes...

Anilines are usually OK on electron deficient rings: aminopyridine, aminobenzoic acids, aminobenzenesulfonamides, aminobenzonitriles etc.

Aniline on el-rich ring is bad news, the most toxic aniline metabolites are aryl hydroxylamines and quinones. On the el-rich rings, the tertiary anilines that cannot dealkylate easily to aryl hydroxylamines (aryl morpholines for example) tend to be less problematic than simple alkylated anilines.

By the way, nitro groups are generally considered unacceptable but they are far less problematic than people believe. Many old (and reasonably safe) drugs have nitro groups. The fear-mongering about anilines and nitros started in big pharma cover-my-ass attitude: "we cannot afford the potenital tox liabilities"

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7. Derek Lowe on June 16, 2009 3:55 PM writes...

Milkshake's right. In more conservative organizations, you may even have trouble pushing the electron-deficient ones, but methoxyanilines, et al., will probably only be advanced by the brave and/or the desperate.

And we may well be missing some useful compounds with that attitude. But it's all a matter of percentages, as I was saying. You can't work on everything, so you pick your fights. A problematic structure might be worth it if the potential need for it is great (see Taxol, torcetrapib).

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8. Hap on June 16, 2009 4:44 PM writes...

I think that the arylnitrenium ions derived from arylamines (by oxidation followed by ionization in acid) are not very nice at all. Arylamines used/previously used in the rubber industry such as benzidine, aminobiphenyl, or the dreaded naphthylamines are all considered to be decent to good carcinogens (and not coincidentally, the cited compounds all seem relatively electron-rich - ionization of hydroxylamines or other N-leaving groups ought to be assisted by electron-donating substituents and hindered by electron-withdrawing ones).

There may be some funny details (one of the articles I found, for example, talked about the N-glucuronides of arylamines (oxidation products? N-hydroxylamines?) being prone to nitrenium ion formation but not the O-glucuronides), and I don't understand why 2-naphthylamines are bad while the 1-naphthylamines are considered so, but arylamines (at least electron-neutral or -rich ones) seem like a toxicological minefield.

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9. milkshake on June 16, 2009 7:00 PM writes...

I remember reading abstract about betanaphtylamine genotoxicity and it was definitely the metabolic activation that made it bad. These compounds are not as awful carcinogens like epichlorohydrine or dimethyl sulfate or nitrosamines, and they actually have a low acute toxicity. The problem was that they used to be so cheap and wide-spread because of the use in dye industry and some people with chronic exposure to these anilines developed characteristic tumors.

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10. processchemist on June 17, 2009 2:09 AM writes...


I hear that most compounds are very specific until biology makes a further step and shows that they hit also other targets (a common problem with kinase inhibitors?)...
About ugliness: a totally impossible-to-be-produced-in-a-really-economic-way-and-short-times product was (and still can be) ugly... I think about discodermolide and heparanase inhibitors (fondaparinux, idaparinux)

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11. Petros on June 17, 2009 2:19 AM writes...

On Hap's point it's Acylglucuronides that are abig problem, it's the rearrangements that they can undergo.

And I can totally concur with Derek's original point. I remember trying to argue the case for a a series of 1-benzyl-4-phenylcyclopentanetriones. Pretty selective and even suprisinly acceptable in preliminary tox but the ugliness arguments- e.g. Michael accceptors, were rife.

On the other hand my most succesful synthesised compound , dropped in PII, was so clean that the tox studies wiped out all supplies of compound trying to find a dose at which any toxic effect could be seen!

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12. Cellbio on June 17, 2009 3:06 PM writes...

back @ process chemist

yes, true that biology messes up bueatiful theories, which is why some choose not to measure more biology, as if ignorance will help with tolerability.

In my prior position, we screened biology at scale, and actually faster than, in vitro counterscreens. Our broad biological data was more informative about kinase program molecule selectivity than kinase panels.

Intersting observation to me was that chemists were eager to have the biological view of specificity, biologists (immunologists) much more cautious about having a liability revealed.

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13. processchemist on June 18, 2009 6:11 AM writes...

@ cellbio

The most successful compound I worked on recently comes from a (small) screening on animal models: in vitro tox not so good, in vivo tox (acute and chronical etc) and potency excellent (for me, an heavy work on scale up)

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