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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: derekb.lowe@gmail.com Twitter: Dereklowe

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September 15, 2010

Intermediates

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Posted by Derek

Talking about the amounts of compound to submit as a medicinal chemist brings up another topic. In every med-chem department I've worked in, there have been periodic exhortations for the chemists to register their intermediates. But too few people do.

For those outside the field, what I'm referring to are the "stepping stone" compounds along the way to structures that you're actually targeting. We try not to have these pathways go on too long, but there are often compounds that lack a key methyl group, or don't have the right stuff on the nitrogen yet, and so on. From the way that the compounds in a project have been running, you can be pretty sure that these things aren't going to be of much use for your current biological target - but the point is that they could be useful for someone else.

I've always been surprised by how many compounds sit on the benches, or in drawers, and never quite make it into the compound repository. To be sure, there are plenty of intermediates that shouldn't go in there - anyone who compound-codes a red-hot acid chloride should be whacked over the head. But plenty of things that people think of as "just starting material" or "just an intermediate" have nothing wrong with them, and should be added. I don't even mind a Boc group on an amine - t-butyl's not anyone's favorite, but there are plenty of drugs out there with carbamates on them. Fmoc is where I'd draw the line, though, since I think there's too much of a possibility for the binding to be driving by that big ol' fluorenyl, which is the first thing you'd want to get rid of if the compound hits. I don't think I'd go for any silyl groups on the alcohols, but benzyls and the like are fine.

So do a good deed today if you're in the lab: clear out a few of those compounds you have sitting around and put numbers on 'em. In your heart, you know it's the right thing to do!

Comments (16) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. BFS on September 15, 2010 8:55 AM writes...

In my former career, the amount of compounds registered, both intermediates and finished targets, were a quantifiable determinant of how "productive" we'd been when it came to yearly performance appraisals. We registered eveything.

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2. You're Pfizered on September 15, 2010 9:23 AM writes...

I've always tried to send core materials/intermediates that are no longer being used into the repository, and I've made pretty good use of some interesting stuff I've found while trolling the database. I've always been shocked that more chemists here don't do this. More for me.

The one drawback, I decided to go on a cleaning streak a few years back, submitted a bunch of intermediates I had and then promptly got laid off a month later. I don't do mass submissions any more, just in case.

;)

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3. BioBrit on September 15, 2010 10:19 AM writes...

Totally agree, it is always good practice to submit intermediates, except those you know are reactive or will give false positives. You mention the (altruistic) reason that you never know what it will be useful for. However, it is also good science for your current project - you eliminate the possibility that any activity is coming from trace intermediate.

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4. Numbercranker on September 15, 2010 11:17 AM writes...

Yes, we were judged by metrics that included the number of compounds submitted so yes indeed, anything and everything got packed up. Not that its a bad thing, very good for the screening library. Hey, if you happen to have a funky acid chloride and don't want to submit it, why not parse it into 8 or 12 vials and add a handful of amines to it, wash and crash out the product and submit them. Now you have multiplied your productivity by X10!! Just sayin.....

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5. MedChem on September 15, 2010 11:28 AM writes...

I would do a lot more of this if we didn't have a very high purity requirement for intermediate registration.

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6. GladToMoveToProcess on September 15, 2010 12:15 PM writes...

We were expected to submit samples of all stable intermediates. For known compounds, ir, nmr, mp, and a tlc system were the drill; for new compounds, elemental analysis as well. It was a pain, but it made writing the papers a lot easier. Once in a great while, an intermediate would do something interesting in the screens.

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7. Daniel Levy on September 15, 2010 1:23 PM writes...

One of the strategies used in the advancement of structure activity studies is to determine the minimum structure required for significant activity. In many cases, such studies are facilitated through assaying the intermediates involved in a given series. As a general practice, I encourage registration and testing of all intermediate compounds.

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8. quintus on September 15, 2010 1:27 PM writes...

Every 3 months we submitted all of our compounds and intermediates to Agrochemicals (when we had that division). Laterly I was submitting the penultimate 2 compounds for screening
It's a good idea to do this.

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9. petros on September 15, 2010 3:16 PM writes...

The Agrochem division of the WDF used to submit some lovely compounds for registration

Hideous structures and purity 10% on occassion

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10. Hap on September 15, 2010 4:18 PM writes...

What is the point of "10% purity"? Does it mean that a) "my desired compound is 10% of this sample, and the other 90% is unreacted starting material/degradation products/crap", b) "the major product is 10% of the sample, with at least 10 other products in diminishing fractions", c) both a) and b), or d) "this was some floor wax I scraped up on the way to work that might do something. Good luck." Or something else?

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11. YellowBuzz on September 15, 2010 8:35 PM writes...

I also work at a place where intermediates are counted exactly the same as a final compound. While this is arguable good for the screening collection, I've found it is terrible for overall productivity. Here is what I see happen a lot: a chemist is assigned a 5 step synthesis; they have trouble with the chemistry, but manage to submit 10-20 mg of each intermediate along the way. Invariably, they end up with less than 1 mg of the final target. There either isn't enough material to get any data or there isn't enough to answer all of the questions that were supposed to be addressed through the synthesis of that target.

End result after 1.5 month: Zero progress for the program, but the chemist looks like a hard worker because they submitted 5 new compounds!

In this manner, a tremendous amount of time and money is wasted "enhancing the screening collection" and then even more is wasted having to sit through meetings where we discuss why we can't seem to make timely progress in any of our programs.

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12. gippgig on September 16, 2010 2:00 AM writes...

This is off topic, but it does relate to drugs. Is this sort of thing of any interest?
Channel 9 (WUSA) in Washington, D.C. is airing a new TV show about biotechnology called "BioCentury This Week". The first show (8:30 AM EDT Sept. 19) is about "the risks and benefits of drug safety measures". I don't know if there is any way to get this outside of the Washington area.

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13. You're Pfizered on September 16, 2010 8:16 AM writes...

I always thought that the compound counting culture was more subtle than what has been talked about in this thread. One of those things looked at behind closed doors, but nothing actually formalized.

I can't think of a less useful productivity metric than total number of compound submissions per scientist. And we wonder why compound collections are full of garbage.

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14. HTSguy on September 16, 2010 12:06 PM writes...

In several cases, the most useful hits we found for difficult targets were intermediates (typically on the smaller side) from other programs.

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15. yo flaco! on September 16, 2010 2:03 PM writes...

The problem with submitting old intermediates as building blocks or sub-structure screening additions is that the registration process, (whether analytical is required or not), is about as mindless as assembling GI Joe dolls at the toy factory. A highly trained monkey could come into my lab and clear out 300+ historic intermediates, but in this “transformed” big-pharma environment there simply isn’t enough time for me to do the work. Anyone who can hook me up with a security cleared primate who will work for bananas will deserve my everlasting adoration.

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16. Sam Weller on September 17, 2010 9:14 AM writes...

It is not just the intermediates, but also how to make them. Don't think only about those compounds that sit in someone's drawer, think about all the work that was invested in designing their synthesis. Now imagine that all the successful (and even the failed) reactions were somehow available to the chemists in the organization in a system such as Reaxys or Scifinder, wouldn't that be useful? There are actually systems that allow chemists to take advantage of such corporate knowledgebases: ARChem by SimBioSys and ICSynth by InfoChem are probably the leading tools in this arena. Of course, they require the chemists to document their work systematically, but nowadays that e-lab notebooks are available, very little is required to generate reactions and compounds databases.

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