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Derek Lowe The 2002 Model

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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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« And Now Some Politics | Main | Ugliness Defined »

June 15, 2009

Don't Make Them in the First Place?

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Posted by Derek

I've been involved in another outbreak of the perennial debate about what kinds of compounds medicinal chemists should be making. I can summarize the way this usually goes:

Chemist A: "Look at all these ugly molecules! Why can't we institute some sort of "No-Suzuki-Coupling" rule for two days out of every week or something? Failing that, why doesn't everyone at least try to make things that look better from the start?"

Chemist B: "Nice thought - but the most potent molecules tend to be on the uglier end of the spectrum. And once you've made a single-digit nanomolar compound for the first time in a new project, it's impossible to walk away from it. It's almost like you get to choose: good physical properties, or good activity and selectivity."

Chemist A: "Don't look in these places if you don't want to find what's there. I'm tired of people making big insoluble monster compounds "just for SAR purposes". Because then some of them hit, and you're stuck with 'em."

Chemist B: "But I can't go give a project update and say that we found the most potent compound ever, but we're not going to follow up on it. And then spend the rest of the time telling everyone that we made a whole bunch of compounds with great properties, but hey, they have no activity. That's not going to do me (or anyone else) any good, right?"

Chemist A: "That's why you don't make the uglies in the first place, so you don't get put in that bind. Of course, what everyone says to do is to take that potent ugly compound and make it better, now that you've found it. Problem is, most of the time the things you do to make it "better" start to kill the activity. We'd be better off with fewer hot compounds, as long as the ones we had were decent."

And so it goes. This same debate has gone on in my other workplaces, too, and I believe that it's a general one across the industrial labs. Who's winning the argument at your shop?

Comments (22) + TrackBacks (0) | Category: Life in the Drug Labs


1. CMCguy on June 15, 2009 9:44 AM writes...

I believe you are right that is fairly general debate although most of what I have seen is "chasing potency first" with dominate attitude "let the Formulation Group worry about delivery" issues. Also frequently correlates to synthesis route where design is good for bench but not so appropriate for scale-up. Usually the latter approach can be circumvented by chemical process work however the former is much more difficult and even though have seen Form Dev come up with usable solutions (literally) one hopes that the med chemists could learn that the molecules they choose can substantially impact course ahead. Ideally you have R&D managers and experienced staff that can temper the direction as to advance progress but make choices that can potentially lead to better candidates.

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2. porkPieHat on June 15, 2009 9:56 AM writes...

Wayne Gretzky once said "You miss 100% of the shots you never take".

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3. Lu on June 15, 2009 10:27 AM writes...

How do you define "ugly" anyway?

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4. Jim T on June 15, 2009 11:01 AM writes...

I've seen enough molecules I was sure would be brick dust (or vice versa; and this goes for other properties - metabolic stability, volume, etc) to know that I shouldn't make assumptions about "ugly".

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5. Alf on June 15, 2009 11:13 AM writes...

Sounds like whining and rationalization to explain why projects are not making better progress. I agree with Jim T. When I hear people talk about "ugly molecules" it raises the hair on the back of my neck. I think medicinal chemists way over estimate how their personal aesthetics map on to drug activity.

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6. CHEMS-R-US on June 15, 2009 11:52 AM writes...

Preliminary in vivo activity rules the day. If a compound has some oral activity, regardless of other properties (beauty, rule-of-five, scalability, etc) it generally gets 'tossed over the wall' to formulation/process chemistry/etc to deal with those issues. They love us and hate us for it at the same time

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7. Norepi on June 15, 2009 11:59 AM writes...

#2: The head of my research group used to say "you miss 100% of the shots you don't take; and 90% of those you do."

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8. Ed on June 15, 2009 12:04 PM writes...

What annoys me is when I make something slightly out of the ordinary or uncoventional and some biology wonk decides they don't like it so it doesn't get tested. Grrrr!

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9. Anonymous on June 15, 2009 12:07 PM writes...

# 3: Derek probably wants to refer those compounds as ugly, which are potent in vitro, but devoid of good ADME properties (and hence good efficacy in vivo)
In my company, if we are the first (forerunner) to work on a particular novel target, importance is given to identify potent compounds in vitro, which are often ugly. The property (lead) optimization comes as a later part. But, in the case of those targets, where we are the late runners in the race, the focus is both "potency+property", so that we can come up with a better candidate (often quickly) than the competitors.

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10. milkshake on June 15, 2009 12:34 PM writes...

If you start with a potent-but-ugly CNS series and hope to optimize it later on for brain penetration, all I can say good luck to you

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11. HelicalZz on June 15, 2009 3:22 PM writes...

I have not really been involved in this issue much, but the answer seems somewhat intuitive.

By all means make the uglies, but early-on. Don't be cranking out impracticals on the third turn of the SAR wheel, when refinement, not re-exploration is the order of the day. Knowing the product development cycle and timeline as well as the expectations (and temperament) of direct and top management is important.

Chemist A - sits in too many meetings
Chemist B - needs to sniff the air outside the hood

They can indeed (and often do) agree at some point (like at the date when the project either advances or gets cut).


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12. Brian on June 15, 2009 3:53 PM writes...

I'm not a chemist, so I don't understand exactly what you mean by "ugly" in this context. Why would someone want to avoid a promising avenue of research just because it is aesthetically displeasing?

I am a programmer. We complain about ugly code all the time, and would much rather have every piece of software be a masterpiece of elegance and beauty. But you can't always be elegant and still accomplish the end goals.

Sometimes, the path of ugliness is the only one that leads to the destination.

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13. Cloud on June 15, 2009 4:13 PM writes...

@Brian- I think Derek is referring to things that are difficult to make/work with. Sometimes one of these compounds turns out to have good activity, and the chemist is now doomed to working with the thing. Sure, its possible, but its not easy and may not even be fun.

I think the programming equivalent is the feature a user insists they need that is going to either require a complete refactoring of your code or a confusing work-around that will trip you up and quadruple the effort every time you have to revisit that portion of the code.

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14. barry on June 15, 2009 4:15 PM writes...

I was involved in writing screens to avoid buying small molecules for our screening library. Some compounds (alkyl iodides, organomercurials, acyl fluorides..) are obvious uglies that will light us some screens but that we wouldn't follow up even if they did. Some (quinones...)are well precedented in drugs on the market. They have proven useful as tools (e.g. geldanomycin) to get co-crystal structures with our target proteins, even though we wouldn't go forward with a drug cmpd that kept such features.
I therefore advocate more nuance here. Some cmpds should be excluded from your screening collection. Some others should be kept only as tools. Some (peptide aldehydes...) should be made and screened with the full knowledge that they will never be drugs, but may still be tools along the way. That requires that we as medicinal chemists educate the biologists around us. No one said it would be easy!

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15. JC on June 15, 2009 5:04 PM writes...

Fix it later with teh prodrug.

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16. srp on June 15, 2009 6:51 PM writes...

This type of argument reminds me of what I've read about disputes over the best path for fusion power. The tokomak people say that their approach is the closest to reaching breakeven and ignition; the advocates for alternative technologies say that it doesn't matter because even if a tokomak overcomes the physics problems its engineering and economic ugliness will prevent it from ever producing commercial power.

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17. milkshake on June 15, 2009 7:07 PM writes...

The acceptability of ugly molecules depends on the drug indication. Most antibiotics and nucleotide-derived antivirals belong into the ugly category. Some anti-asthma inhalable drugs are ugly too. (Not mentioning the chemotherapy drugs.) You can get away with lots of unsightly things if you don't need cell permeability or good metabolic stability

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18. Anonymous on June 15, 2009 8:44 PM writes...

I think that Derek is invoking 'ugly' in terms of performance rather than aesthetic dimensions, somewhat in the vein of 'ugly is as ugly does'. My opinion is that most often the activity of such compounds is fool's gold and serves to distract us from real drug discovery. While some of the uglies can be fixed through thoughtful optimization or (less optimally) formulation, most prove refractory to our best efforts. I am increasingly choosing to pursue compounds with biophysical properties more favorable for translation into in vivo settings, even at the expense of a log or two in IC50.

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19. CMCguy on June 15, 2009 9:04 PM writes...

milkshake's comment does reflect "beauty is in eye of the beholder" which is indeed partly true and adds to the complexity of discovery efforts. What's ugly to some may be attractive to others and what is tolerable to certain applications may not work for other programs. As others suggest can be influenced by where one is in a project yet does seem once get zoned in it can be difficult to improve in certain aspects without adverse impact in others.

#11 ZZ sounds nice in principle but these days expectations of management is frequently not conducive to "iterative" prep/test/review as timelines force paths to what can get done verses what want to do.

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20. Lucifer on June 15, 2009 11:24 PM writes...

Pfizer Violated Own Rules to Hide Depression Drug Studies

By Jim Edwards | June 12th, 2009 @ 11:38 am

Pfizer is accused of “deception through concealment” and “cheating” in failing to disclose nine of 16 trials of an antidepressant, Edronax (reboxetine), in Germany. The German Institute for Quality and Efficiency in Health Care slammed Pfizer in a press release titled:

Pfizer conceals study data; Drug manufacturer hinders the best possible treatment of patients with depression

Essex Pharma was also noted for not being completely upfront about its antidepressant, mirtazapine, and the Institute praised GlaxoSmithKline in the same set of statements for providing a full database of studies for bupropion XL.

Pfizer’s refusal to disclose its studies violates its own published policy about studies. That policy states:

In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and complete manner and are reported regardless of the outcome of the study or the country in which the study was conducted.

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21. Anonymous on June 16, 2009 2:10 AM writes...

With only a couple dozen NCEs approved each year we shouldn't be too confident in any sort of "policy" about how to pursue drug discovery.

Let the scientists on the front lines decide what is the best course for their particular project at it's particular stage.

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22. LeeH on June 20, 2009 10:18 AM writes...


I agree with your general aversion to making "ugly" compounds. The medicinal chemist lives and dies by his/her ability to recognize patterns (and turn them into chemical matter). I think the big difference among the attitudes on this issue comes from how people react to experience.

Some people have been involved in successful programs that have advanced a compound with chemical functionality that is considered questionable. Note the nitro guanidine functionality in ranitidine. Those people might have a higher tolerance to ugly compounds, and will never meet a molecule they won't like.

Others, probably a larger group, have tried to advance an ugly compound compound and have been beaten down. Once bitten, twice shy.

Some will look at drugs overall and say "Look. There are uglies. So it can be done. So I'm not afraid." Others will look at the same set and say "Most drugs are not ugly. So I'm going to avoid uglies, since statistics are on my side."

As an experience modeller, my feeling is that those that those that ignore history are doomed to repeat it. But this is a statistical argument. Make lots of bad bets, you'll lose overall. But don't throw out a particular compound that looks ugly but somehow seems to defy the odds in terms of ADME/PK. Just be aware that your luck may run out at some point.

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