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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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« Model Systems, From Inside and Out | Main | Through the Looking Plastic »

January 19, 2005

Bonfire of the Wonder Drugs

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Posted by Derek

I'll be occupied on and off in the next few months with writing several scientific papers (nothing wrong with bulking up the ol' resume, especially in this climate.) There's always the question of which journal to fire these cannonballs of wisdom towards. Two factors compete: where you'd ideally like to see the paper appear, and where you realistically think you can get it accepted. You aim for the intersection of those lines.

Sometimes the answer is clear - for example, if you've got a comprehensive report on a fairly new diabetes therapy, a good solid paper from discovery to clinic, you're probably going to send it to Diabetes. The situation is more complicated at the higher and lower ends of the scale. A startling head-turner of a paper has a number of venues to choose from, depending on its focus and who you might know in the various heirarchies - Science, Nature, Cell among others. I won't be sending any of this year's papers to those folks, sad to say.

You'd think that the premier journal in medicinal chemistry would be the Journal of Medicinal Chemistry. It may well still be, and I'm sure that the American Chemical Society (its owner) thinks so. I need to check this out, but it's my impression that the journal has had a shrinking percentage of industrial papers in it over the years. Some upstarts have siphoned off some of their raw material. A particular competitor is Bioorganic and Medicinal Chemistry Letters, which began life (and still spends a good part of its time) as a dumping ground, but has slowly changed into something more.

One big difference between the two is that J. Med. Chem. publishes both full papers and short communications, while BOMCL features only the latter. (That's the meaning of "Letters" in scientific publishing.) A full paper naturally includes a full experimental section, with preparative details of all the compounds and their physical characteristics. And there we come to the real split between the journals. For a full paper, J. Med. Chem. wants more details than I happen to have.

They want combustion analysis on important compounds, and I just flat out don't get that level of data on most of them. That's a primitive-sounding (but, in theory, very effective) method of checking a compound's purity. You burn a small sample of it and carefully measure the amount of carbon dioxide, water, etc. that come off. That gives you the percentage of the compound's weight that was made up of carbon, hydrogen and the other oxidizable elements, which is why we often call it a "CHN" analysis.

Then you see how well the experimental value matches up with your theoretical amounts. It comes out to a couple of decimal places, so you can distinguish pretty close matches, in theory. In practice, the compounds usually have to be thoroughly dried and handled carefully before this test, because many of them will soak up a bit of water from the air. Some of them actually crystallize with water molecules in their lattice, as part of the repeating crystalline pattern, and combustion analysis is a good way to see if your compound has done that. It also means that if you're willing to assume, say, one/third molecule's worth of water of crystallization, or some damn such, you can finagle the numbers to come out to most anything you need. (Mind you, a whole paper's worth of such fudge-factoring would get a frosty reception.)

But, for the most part, I don't care very much if my compounds combust well. During a drug discovery project, we don't have time (or material) to send samples away to be analyzed (it's a specialized job.) We rely on NMR (proton, some carbon) and the combination of HPLC and mass spectrometry. Those are enough to characterize a compound for a patent (well, except for some outlier countries like Taiwan), and they're enough to convince us that we've made the right thing and affect the expenditure of millions of dollars. But it's not enough for J. Med. Chem.

Well, not until recently. They've slowly been loosening the noose the last few years, offering high-resolution mass spectral data or data from two different HPLC systems as alternatives. Not that we usually have those, either, but it's a start. But I think I'll let the combustion lab do the work: if I'm going to be sending J. Med. Chem. anything this year, I'd better start getting ready for a Wonder Drug Barbecue.

Comments (3) + TrackBacks (0) | Category: The Scientific Literature


COMMENTS

1. chemist on January 19, 2005 9:57 PM writes...

That was an interesting insight. I have also wrestled with this topic on a few occasions. The conclusion I came to, is that there are the following papers published in J. Med. Chem.

1. I did a QSAR or modelling study and have some pretty pictures (How far does that really get us in drug development anyway?)

2. It is a paper from a major pharmaceutical company with excellent results AND an experimental section AND CHN analysis (typically a japanese company fulfills ALL three criteria)

3. I made a bunch of nucleosides or some strange compounds and they are somewhat active but will never make it as a drug (but I have experimental and CHN analysis!)

I gave up and send my stuff to BMCL. I agree that it is somewhat of a dumping ground but there are good papers in there which really stand out AND I dont have to spend time writing an experimental AND get CHN analysis.

I think J. Med. Chem needs a new editor (sorry no offence) who works in industry and understands that we spend enough time characterizing our compounds to spend a bunch of money testing them in a bunch of animals.

Although, I do plan to do something brave this year - submit a communication to J. Med. Chem with only proton NMR and HPLC/MS data!

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2. David Govett on January 20, 2005 12:20 AM writes...

Sounds like someone needs to program an AI-based journal identifier. Perhaps an evolutionary algorithm could evolve the right choice. I'm serious...really...I am.

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3. PharmaChemist on January 20, 2005 8:29 AM writes...

I am not sure that J Med Chem understands what an impediment the requirement for elemental analysis, or for that matter HRMS, is for researchers to publish in that journal. The thought never crosses my mind to publish there because of that requirement and I know that I am hardly alone in my sentiment. In fact, I get a bit antsy when those in my research group tell me they plan to publish in J Med Chem because I know how much time will be devoted to obtaining less-than-critical data in terms of what is needed for successful drug discovery. If CHN wasn't required and J Med Chem had established an adequate letters section I wonder if BMCL would have been as successful as it has been.

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