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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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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

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October 27, 2008

Publish And Be Damned, Most Likely

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Posted by Derek

As I’ve mentioned here before, publication in the scientific journals is not necessarily a big priority in the drug industry. Patent filings, on the other hand, are very serious business indeed. If you’re an organic chemist looking to see if some particular compounds have been made, you ignore the patent literature at your peril. That’s where most of our med-chem procedures and analogs end up, and there’s a lot of good chemistry in there that never sees the light of day otherwise. Most of it’s even reproducible! (And that’s a crack that you can make about a number of open-literature journals, too, for that matter).

But we do write up papers from time to time. The problem is, it’s often only after the project has been finished for a while. Sometimes it takes that long to decide that the work is safe to publish, and sometimes there are just too many other (more important) things going on. But the result is the same, and I’ve experienced it myself: you go back to the old project data, ready to assemble it into a manuscript. . .and large sections of it appear to make no sense at all.

It’s disconcerting. By “no sense”, I mean that while the chemistry is fine, and the compounds are what they’re supposed to be, it’s nonetheless hard to see why some of them got made in the first place. Whose idea was it to react that amine with every single isocyanate on the whole shelf? None of the resulting ureas were all that good, so why did we decided we needed seventy-nine of them? And there are always gaps in the story that weren’t so apparent while things were going full speed: how come we never made any more of those N-alkyl compounds? And didn’t we resolve that series of racemates at some point? Somebody was supposed to do that.

All this makes it hard to turn many med-chem projects into coherent stories, and a coherent story is what you'd like for a journal publication. Ideally, you want a narrative, something along the lines of: ”We started with this screening hit – promising, but lacking so many key things. By careful, thorough experimentation, we solved those problems one after the other. Moving from strength to strength, and hardly wandering down any blind alleys at all, the analogs became more potent, more selective, and their physical properties and PK fell right into line. In the end, we prepared the wonderful clinical candidate shown in the last table of data on the last page. Not too obvious, is it? Bet you wouldn’t have gotten there yourself. But that’s how good we are.”

Right. The problem is, no projects ever work like that. Or if they do, I've somehow missed seeing them over the last nineteen years. A more realistic story would go something like: “We started out with this screening hit, and decided that we’d change the right-hand side of it – well, the left-hand side, for those guys down the hall who always drew the thing upside down and drove the rest of us crazy. That’s the part of the molecule that had the easiest chemistry, naturally. And naturally, everything we did to it over there made things worse. So the weeks went by, with management tapping their feet, and finally some of the guys said the heck with it and started changing the back end of the molecule. You thought those other compounds were less potent? You should see these! But one of the changes actually worked, for some reason. Then when we went back and starting messing with the easy side of the molecule, two things happened: for one, the chemistry wasn’t so easy any more. But now those changes actually made things better. So we cranked out a whole pile of these things, hoping for the best, and finally got down to two compounds: one with great potency and selectivity, but iffy blood levels, and one with great PK, but not so great on the potency. Never could bridge the gap. We put ‘em both into two-week tox, and they both flunked out for the same completely unexpected reason. They're not gonna be drugs, we've filed the patents already. . .so, here they are!”

Well, you can’t quite say that, not even in Bioorganic and Medicinal Chemistry Letters. So you put things into the most coherent shape you can, and trust your fellow medicinal chemists – those of them who might actually read your paper – to understand. They generally do.

Comments (13) + TrackBacks (0) | Category: The Scientific Literature


COMMENTS

1. petros on October 27, 2008 8:29 AM writes...

So true. And company policy can further delay submission. Some work I did on anti-allergic drugs ( a hot topic in the late 70s/early 80s in J ed Chem) couldn't be submitted until a development compound had reached phase II or the project abandoned. Since it took about 6 years for the project to be killed I'd lost interest in submitting it.

Another factor is the requirement that J Med Chem had for a long time for characterization by microanalytical data, long after many companies had stopped using such methods. That meant that either the authors' lied about having such data (it did happen) or BMCL was the best available option

Permalink to Comment

2. ... on October 27, 2008 9:48 AM writes...

Where is the best place to access patents online? I live and work in the academic world (en route to industry) and patents are still a thing of mystery to me. What search resources do you use to search through patents (Scifinder?).

Permalink to Comment

3. RB Woodweird on October 27, 2008 10:27 AM writes...

Number 2, try Google Patents. You can download the whole thing at once and search within a found patent for text before downloading. It makes the previous ways I used to search patents look like toys.

Permalink to Comment

4. devices r us on October 27, 2008 12:31 PM writes...

google patents is very very much a beta. Most of the advanced options don't work (like inventor name) at least on IE. You can just go to the uspto.gov site and do a bunch of searches for free. Beware though, many many patent lawyers don't go out of their way to make searches easy. We were looking for compounds that reversibly bound glucose. Found a patent by accident, didn't mention the word glucose in spite of the fact that the whole patent was about sensing glucose. It did talk about cis-diols though. Sometimes makes you crazy. Also if there are lots of examples, believe the first ones, the later ones might be "prophetic"

Permalink to Comment

5. Sili on October 27, 2008 2:57 PM writes...

Well, you can’t quite say that
Pity, really. It'd make reading more interesting.
trust your fellow medicinal chemists to understand. They generally do.
And then they're the rest of us he never cottoned onto that and stayed too naïve for their own good. Permalink to Comment

6. Chrispy on October 27, 2008 6:34 PM writes...

One of the things I have observed is that in Departments where publication is not encouraged the quality of the work goes down. People are always in a rush to get things done, and so a lot of what gets done are experiments of the "quick and dirty" variety which could never get published. Keeping publication in mind at every stage of research enhances the quality of the work. It also affects the quality of the people the Department can attract...

Permalink to Comment

7. Greg Hlatky on October 27, 2008 10:00 PM writes...

The best place I've found to access patents online is the European Patent Office website.

http://ep.espacenet.com/

Permalink to Comment

8. drug_hunter on October 28, 2008 5:04 AM writes...

I've always wondered how often a large series of related compounds are made (like Derek's example of "every single isocyanate on the shelf") simply because the reagents are available and the chemistry is already worked out? In other words, for "lazy" reasons. I've certainly seen that; how common of a problem do you all think this is?

Permalink to Comment

9. Eric on October 28, 2008 7:23 AM writes...

SciFinder provides access to records from chemistry related patents back to the 1800’s. Coverage is summarized at http://www.cas.org/expertise/cascontent/caplus/patcoverage/

Permalink to Comment

10. john.spevacek@aspenresearch.com on October 28, 2008 7:44 AM writes...

Derek's post should be required reading for all new grad students or anyone else making their first brave attempt at reading the literature. While I now appreciate the whitewashing that goes on in published results, it can appear very intimidating to the non-initated, making it appear as if the researchers had the foresight to make significant progress in ALL of their experiments and NEVER went down any blind alleys.

Permalink to Comment

11. Don B. on October 28, 2008 8:13 AM writes...

The usual reason someone reacts all of the isocyanates in Aldrich with their amine is that some "VP of R&D" has set a compound number "GOAL"!

Permalink to Comment

12. Anonymous on October 28, 2008 2:46 PM writes...

Going back and trying to assemble a manuscript is one thing, finding a competitor's patent of selection based around some compounds you were SURE you exemplifed (or that you KNEW wouldn't be active so went to the bottom of the list) brings tears to your eyes.

Permalink to Comment

13. RTW on October 29, 2008 8:45 AM writes...

This is all about knowledge management. Something these organizations do a very bad job of. Knowledge resides in individuals heads, and is not captured in the organization in any meaningful search-able or organized manner that will enable transfer to others.

Anyone says all this goes into databases are naive. It becomes disconnected data that requires the knowledge be rediscovered and the connections be re-established. This is where Dereks example sits. Why did we do this? Data is in the DB, but the connection (causal Why?) is missing. As a medicinal chemist I saw this happen all the time in my 20+ years.

So I tried to do something about it by creating MedChem project web pages for my organization that captured voluntarily and quite painlessly I might add, all the information we could about the projects being worked upon. It was not a burden, it was well organized in a particular framework created by a medicinal chemist rather than an IT professional, with a great deal of consultation with the scientists using it. It was quite successful and used on a voluntary basis.

The system captured a great deal of the whys, plans, actual meeting minutes, and data organized and properly plotted with their connections for the project. Not just discreet data collection. Its was all nicely wrapped up, and available during the project as well as after a project was completed, just in the (often likely) case the project might be restarted with vastly different personnel at a later date.

I am available for consultation. ;-)

Permalink to Comment

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