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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 26, 2010

Privileged Scaffolds? How About Unprivileged Ones?

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Posted by Derek

The discussion of "privileged scaffolds" in drugs here the other day got me to thinking. A colleague of mine mentioned that there may well be structures that don't hit nearly as often as you'd think. The example that came to his mind was homopiperazine, and he might have a point; I've never had much luck with those myself. That's not much of a data set, though, so I wanted to throw the question out for discussion.

We'll have to be careful to account for Commercial Availability Bias (which at least for homopiperazines has decreased over the years) and Synthetic Tractability Bias. Some structures don't show up much because they just don't get made much. And we'll also have to be sure that we're talking about the same things: benzo-fused homopiperazines (and other fused seven-membered rings) hit like crazy, as opposed to the monocyclic ones, which seem to be lower down the scale, somehow.

It's not implausible that there should be underprivileged scaffolds. The variety of binding sites is large, but not infinite, and I'm sure that it follows a power-law distribution like so many other things. The usual tricks (donor-acceptor pairs spaced about so wide apart, pi-stacking sandwiches, salt bridges) surely account for much more than their random share of the total amount of binding stabilization out there in the biosphere. And some structures are going to match up with those motifs better than others.

So, any nominations? Have any of you had structural types that seem as if they should be good, but always underperform?

Comments (9) + TrackBacks (0) | Category: Drug Assays | Drug Industry History | Life in the Drug Labs


1. anon the II on March 26, 2010 9:37 AM writes...

My thinking is that this whole privileged structure thing is a bit of a red herring. I suspect that the major contributor to the illusion is synthetic accessibility.

But there is something more fundamental about this analysis that bothers me. Twenty years ago, we kept medicinal chemists around because they could look at a structure and sort of agree "Yep, it looks like a drug" or "Nope, it don't look like a drug". It came from a mysterious combination of intuition about a chemical structure and what it meant to all those ADME properties and whether the molecule was unique enough to be selective, potent, etc.

Over the last few years, there has been a major attempt to codify all this intuition by really abusing the methods of statistics. We've come up with lots of concepts (ie privileged structures) and laws (ie Lipinski), but in the process have severely degraded the perceived value of experience.

We all know the result. "Why would I pay a guy (with 25 years experience) x dollars when I can get a guy (with 2 years experience) for x/5 dollars?"

It's not that we shouldn't engage ourselves in these mental exercises, I think that's how the intuition is developed. It's just that we should be a lot more honest of just how blunt an instrument we're using. Especially, when we're describing it to upper management.

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2. anon on March 26, 2010 11:49 AM writes...

Don't give up on homopiperazines just yet. From the SF ACS meeting first disclosures of clinical candidates symposium....

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3. Sili on March 26, 2010 1:16 PM writes...

I'd completely forgotten about the "homo" naming convention. Thanks for refreshing that bit of useless information.

(Btw, I see Imants's already coded up that 'Ebay rating' for suppliers, I whined about. Anyone looked at it yet?)

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4. milkshake on March 26, 2010 2:02 PM writes...

Fasudil is a very popular drug in Japan and it is homopiperazine.

I would nominate amides of squaric acid as a useless curiosity - they are easy to make and occasionally you see them in paper where they were included for their shock value but nothing ever comes out of it. maybe its the irritant properties of certain squarates that make them unpopular

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5. CrazyDave on March 26, 2010 2:29 PM writes...


Squaric acid amides are supposedly urea isosteres. Merck has one (from the former Pharmacopeia) in several PhII trials (CXCR2).

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6. Cutting Loose on March 27, 2010 8:27 AM writes...

Re. #1

I completely agree: so many rules, so little learning.

(Actually, this is just the latest incarnation of the 20-year project to "industrialise" R&D.... amazing how many of these 'new' concepts can be traced back to the ashes of CombiChem/HTS).

Time for a little less Lipinski, a little more Thinking?

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7. Cutting Loose on March 27, 2010 8:35 AM writes...

Actually Derek, has the time come for a:

"What has 'Lipinski' ever done for us?" thread...?

(No disrespect to the man himself).

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8. mehere on March 31, 2010 9:50 AM writes...

cyclohexyls. the amount of times these get suggested in meetings as a replacement for phenyl, piperidine, piperazine for various reasons. Never works. (this should be a way of summoning up loads of examples where they work beautifully)

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9. barry on March 31, 2010 7:28 PM writes...

re: mehere

Nothing wrong with cyclohexyls. They're all over the HIV protease literature. They're near-isosteres for Phe, not for piperidine or piperazine. Of course most HIV protease inhibitors have bad ADME...

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