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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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July 16, 2014

What Structures Have Turned on You?

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Posted by Derek

When you ask a bunch of medicinal chemists to look over a list of structures - screening hits, potential additions to the compound collection, that sort of thing - you'll find that everyone will cross some of them off. But the agreement between the chemists on which ones need to go, that's the tough part. It's been shown that we don't overlap very much in our preferences, at least when it comes to the structures we'd prefer not to try to advance. That's because we don't overlap as well as we think we do when it comes to the rules we're using.

So here's a question, which might illustrate the point: what compound classes or scaffolds have you been burned by? I think that's one big factor that we all use when we're evaluating one of those compound lists - which ones are in that "Fooled me once" category? For me, a recent experience with NH pyrroles has me reluctant to go there again. And I'm not interested in things with napthalenes hanging off of them, naproxen notwithstanding. I'd also rather not see Mannich products, since I've personally seen a number of those misbehave.

So what's on your list? I think that everyone can agree on things like rhodanines, although even those have their partisans. But what semi-decent looking compounds will you go ahead and blackball, based on your own nasty experiences with them?

Comments (17) + TrackBacks (0) | Category: Life in the Drug Labs


1. road on July 16, 2014 9:15 AM writes...

I first read the title as "What Structures Have Turned You On" and was expecting a much more interesting post!

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2. Anchor on July 16, 2014 9:33 AM writes...

Thioureas! Enough said!

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3. Kazoochemist on July 16, 2014 9:44 AM writes...

Not an answer to your query, but I would like to direct the readers to my prior comment on the paper you refer to in the first paragraph. It is comment number four in the "as we think we do" link. The premise of the work described in the paper as well as the reported results and conclusions are deeply flawed. This is a consequence of the way the lists of compounds were pre-sorted and the selection guidelines given to the reviewing chemists.

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4. Anonymous on July 16, 2014 10:40 AM writes...

Indazoles on grounds of promiscuity springs to mind.

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5. anon the II on July 16, 2014 10:57 AM writes...

I also read the title like Mr. Road (#1) and thought that might be a better column. Jonathan Baell (of PAINS fame) has kinda covered this already. And we mostly agree with what he said plus a few more here and there. So how 'bout a column on what structures that turn us on? Not pharmacologically, but for purely aesthetic appeal.

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6. Anonymous on July 16, 2014 11:29 AM writes...

Dimethyl pyrroles.

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7. Anonymous on July 16, 2014 12:17 PM writes...

Phenethyl amines, tryptamines. Oh wait. Never mind.

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8. Industry Guy on July 16, 2014 12:39 PM writes...

Anything that turns up in the Patent Gazette that I'm currently working on I consider having turned on me....those compounds have no loyalty...

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9. John Wayne on July 16, 2014 3:57 PM writes...

Thiazoles, heteroaryl ketones, and anything that has to be greasy for activity/brain penetration

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10. Secondaire on July 16, 2014 7:14 PM writes...

Imidazoles, with all of their "let's inhibit heme-containing anything!" activity.

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11. Anonymous on July 16, 2014 9:35 PM writes...

imidazole for me too!

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12. Anonymous on July 16, 2014 9:35 PM writes...

imidazole for me too!

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13. Deep Lurker on July 17, 2014 12:56 AM writes...

Back before I took my extra-early retirement, I was willing to go with all kinds of different iffy things. Because you never know, and in my case I did work with some really grotty compounds.

But I was a lot less enthusiastic than my boss about heavily fluorinated compounds, and a lot more enthusiastic about t-butyl groups.

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14. exGlaxoid on July 17, 2014 8:51 AM writes...

I have always liked indoles, piperidines, pyridyls, N-benzyl and phenethyl groups, phenols, CF3s, and even naphthylenes. My turnoffs are carbazoles (all of the problems of both indoles and naphthyls) furans (although a few have worked OK), guanadines (Arg is a pain), polymethoxybenzenes, hydrazones, and steriods (although they are in many useful drugs). Like Derek, I also don't like pyrroles. And thioureas, thioamides, and thioketones are all bad.

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15. Iridium on July 17, 2014 4:26 PM writes...

At one point I worked on a series with a tetrahydro thienopyridine core, which exhibited extremely interesting activity in our primary assay. However, after several months of working with a CRO (little to no internal chemistry) we discovered that the compounds auto-oxidized to the pyridiniums while just sitting on the bench in solid form. Was able to demonstrate that the activity in the assay was linked to the ability of the compound to form the pyridinium. Was never too happy about that...

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16. Lunar landing on July 22, 2014 6:10 PM writes...


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17. Bill Curatolo on August 8, 2014 12:47 PM writes...


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