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Alzheimer's Disease

A Modest Literature Proposal

Looking through the latest papers to show up in the Journal of Medicinal Chemistry, this one on BACE-1 inhibitor compounds caught my eye. Perhaps I’m about to be unfair to it. At any rate, I’m going to ask of it something it doesn’t provide: data in something that’s alive. Doesn’t have to be a person, a dog, or even a rat. A cell would do: something with a membrane to cross, with metabolic processes, and with the ability to accept or reject someone’s new compound. Enzymes just have to sit there and take whatever you throw at them; living systems fight back.
I sometimes think that we’d be better served if each of the medicinal chemistry journals were split. In J. Med. Chem.‘s case, we would then have the Journal of In Vitro Medicinal Chemistry and the Journal of In Vivo Medicinal Chemistry. The criteria for publishing in the two journals would be exactly the same, except to get into the latter one, you would have at least had to have tried your compounds out on something besides an in vitro assay. Doesn’t mean that they have to have worked – you just have to have looked.
Although the case of compounds with molecular weights of 900 that have four amides and a sulfonamide in them, and are directed against a target in the central nervous system, might still be a bit of a stretch. I supposed what irritates me about this paper is that it starts off talking about Alzheimer’s disease. And that’s natural enough in a study dedicated to finding inhibitors of BACE-1, but the problem is, Alzheimer’s disease occurs in human beings. And these compounds do not look to have much chance of doing anything inside any human’s body. The best I can say for them is that they might give someone else an insight into something that they might be able to do to make something that might have a better chance of working.
Cranky folks like me would probably refer to the latter of my two new journals as just “J. Med. Chem.”, and would refer to the former one by a variety of other easy-to-remember names. I offer this suggestion for free to the scientific publishing community, who will, I’m sure, reciprocate with things of equal value.

26 comments on “A Modest Literature Proposal”

  1. Christian Hesketh says:

    Well said!

  2. Anon says:

    The way the ACS is launching journals they might take you up on that!

  3. milkshake says:

    it is from two university labs that trying their hand at medchem

  4. Chemjobber says:

    I don’t know the cost of these assays, but I’m guessing that in vivo assays are more expensive. Would this demand be cost-prohibitive?

  5. What about older HIV protease inhibitors? They also have a similar chemical structure (3-4 backbone amides, large pendant groups etc)

  6. Derek Lowe says:

    Ah, but they weren’t targeted at the brain, and that’s my biggest problem here. And although the structures of saquinavir and ritonavir are pretty ugly, they’re still better than these things (and they weigh less, too).

  7. Ed says:

    Active transport mechanisms perhaps?

  8. anon the II says:

    My first thought was “Isn’t he the guy that got the Nobel Prize for all that prostaglandin work? No wonder he got published.”
    But I guess he’s not. Maybe he’s related.
    To be fair, I know about a BACE-1 inhibitor program a few years back at a company that should have known better, that had leads similar to these.

  9. Anonymous says:

    However, BBB penetration is observed for HIV protease inhibitors and that was a criteria for those of us working in the area. (I also suspect that PGP plays a role in that transfer but I don’t know for sure.) I have also wondered whether sub-efficacious levels in the CNS has contributed to viral resistance to these drugs. (If I had Scifinder, I could look it up.)
    I guess I don’t understand whether you’re looking for this journal to demonstrate in vivo efficacy in an animal model or just getting on board. Where would you draw the line? For some areas, like HIV, there isn’t any reasonable animal model to test. You look at everything you can and hope for the best based on all of your data. Also, small changes in those in vitro assays can dramatically alter their potencies and can be very predicitive of human efficacy. Once again, I can site examples in the HIV area where a compound was micromolar in one assay and nanomolar in another. The compound had good PK but failed in trials. Turns out that if you cut back on your Il-2, your compounds look a LOT more potent than they really are since Il-2 stimulates lymphocyte proliferation. (That’s how you polish a turd and sell it to people with no drug discovery experience for 720 million dollars!)
    I suspect that because of your knowledge and experience what irritates you is the waste of effort on something any experienced medicinal chemist would have never even started. Well, I don’t think that creating a new journal is going to take care of that. Alternatively, we should have higher expectations as reviewers for these journals and be willing to reject stuff that shouldn’t be there. “Medicinal” implies utility.

  10. fragment_boy says:

    My PhD work got published in J Med Chem and looking back its a nice paper but based on what I am putting into papers now (from biotech and currently at an academic drug discovery lab) I am pretty ashamed.
    I agree that J Med Chem is often seen as a journal for ‘professional’ drug discovery groups, and not for the ‘amateurs’ in academia – well thats the view of some folks anyway….
    Access to in-vivo models can be prohibitively expensive for academics, as is DMPK. Academic works shouldnt be discriminated against as some of the work can be very valid.
    The paper highlighted however does not look like the sort of thing that should be in JMC though…….

  11. DeviceRUs says:

    I think that if your only approach to getting something like this to the brain is via the mouth then you might be right. But there are other ways (Convection enhanced delivery) that aren’t maybe do elegant but can get the job done (if the molecule works that is).

  12. Curryworks says:

    Will you use the blog as an open source peer review medium? It seems to have worked I suppose some authors may get a bit upset though.

  13. partial agonist says:

    Maybe they are after that always popular delivery mode, intracranial injection.
    Get in line for that one!

  14. Mark says:

    I think a lot of this has to do with grant writing. In grad school I worked on selenium chemistry that was of academic interest, but it was always spun as a research on treatments for oxidative stress diseases. Made the grant proposals a lot more interesting (and lucrative).

  15. Hap says:

    I think one of the antisense drugs for macular degeneration is given by intraocular injection. It’s better than going blind, but I don’t think I would choose that delivery method otherwise.

  16. researchfella says:

    C’mon Derek, you’re already in cahoots with ACS with the launch of one new medchem journal, don’t even jokingly suggest to split JMC to produce yet another one. We don’t need any more medchem journals, and we can’t afford to subscribe to any more medchem journals. With all the pharma researchers who have been laid off during the past five years, I can’t believe there will be any increase in the number of worthy publications coming out of pharma for years to come. Sad but true.
    By the way, some of us used to call J. Med Chem. “The Journal of Inactive Compounds”, since so many (most?) of the compounds reported seem to qualify for that description, at least in vivo. Hey, I’ve published some in JMC as well, that’s what we do.

  17. cliffintokyo says:

    They have pharmacology journals for that in vivo stuff.
    Just because of your new job-on-the-side, don’t start thinking that Med Chem is destined to take over the Pharma World! P-)
    BTW, I have heard that there is a shortage of experienced pharmacologists who know their stuff, esp. in the US. [Career change anyone?]

  18. London Chemist says:

    If your program fails, you get to publish, if its successful then it could be years before it sees the light of day. Many companies use publications as a means of judging which scientists are “succeeful” (my first employer had a point systems–number of points depended on the journal—to be promoted you needed a certain number of points). Add to that, many more programs fail than succeed–any wonder the lit is full of papers of dubious quality?

  19. Morten G says:

    So BACE-1 has been verified as a target for AD? I thought it was still debated whether inhibiting it would actually have any useful effect on AD progression. If the compound is good and selective you could do i.c. injections in pigs. Maybe find out.
    You really are cranky.

  20. Morten G says:

    That said, the abstract does contain two grammatical errors. That is embarrassing. For ACS.

  21. Evorich says:

    My attitude to publishing tends to be “if it’s real information, publish it”. Data is data!
    If this was a great start-point for med.chem. then we’d all be happen to pick it up for a Bace program. Might still be that if someone can get a crystal structure, determine which parts of it do most of the interacting, and change it to something that might get into a cell or even across the BBB (which this almost certainly won’t).

  22. imatter says:

    I think the article is a perfect example of J. Med. Chem. article. It has drug design, synthesis, analyses, bioassay, SAR discussion, and an xray crystal. The animal studies, if it gets that far, is fair game for another journal. And there are journals out there that would have better set of editors and reviewers than ACS could provide for these types of in vivo studies.

  23. Hap says:

    Shouldn’t a medicinal compound have a chance in hell of entering a living thing, though? The characterization may be nice, but since it isn’t clear that the biology is relevant to its supposed function (and even if it is, the drug may never see the in vivo system because it’s a frickin’ concrete latrine), there’s not much medicinal chemistry there. Someone above made the comment that “‘medicinal’ implies utility”, and that seems relevant.
    It might be useful as a biological tool for BACE inhibition (and thus as a discovery tool), but there are biological journals for those things.

  24. Mike W says:

    This si the kind of crap that should have a hard time getting into BMCL. Frankly, the editor at JMC should have stopped this one from even going out for reviews.

  25. Tok says:

    The QS molecules are quite a bit larger than this one (MW around 2000) and seem to work their adjuvant voodoo very well. Probably don’t need to cross the BBB though.

  26. JOhn says:

    I don’t know Derek, maybe you should have covered this article under your “How we got in this fix” post. The structure is not that different from what was published in dozens of other publications by supposedly first tier big pharma med chem groups, and I’m embarrassed to say that my name is on some of them.

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