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The Difficulties of Drug Research from a Medicinal Chemist Viewpoint

Discussion in 'Other Health News and Research' started by Waverunner, Sep 2, 2012.

  1. Waverunner

    Waverunner Senior Member

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    Here is a very interesting article by Derek Lowe. He is a chemistry blogger and medicinal chemist working on preclinical drug discovery.


    According to him there are two problems when developing drugs. The first problem is that it is unbelievable hard to actually find the right compounds because there are so many things that have to be taken into consideration (one being that we mostly don't even know the exact cause of a disease) and the other being, that is is very expensive to test drugs. On the other side there are critics like Donald Light, who claim that during the last years we have less and less new drug entries into the market. It seems the development process slowed down, while it is more lucrative to change a few molecules of existing drugs and to file a new patent, instead of bringing out new compounds.

    http://pipeline.corante.com/archives/2012/08/09/getting_drug_research_really_really_wrong.php

    ...So let me get this straight: according to these folks, we mostly just make "minor variations", but the few really new drugs that come out aren't so great either, because of their "epidemic" of serious side effects. Let me advance an alternate set of explanations, one that I call, for lack of a better word, "reality". For one thing, "me-too" drugs are not identical, and their benefits are often overlooked by people who do not understand medicine. There are overcrowded therapeutic areas, but they're not common. The reason that some new drugs make only small advances on existing therapies is not because we like it that way, and it's especially not because we planned it that way. This happens because we try to make big advances, and we fail. Then we take what we can get.
    No therapeutic area illustrates this better than oncology. Every new target in that field has come in with high hopes that this time we'll have something that really does the job. Angiogenesis inhibitors. Kinase inhibitors. Cell cycle disruptors. Microtubules, proteosomes, apoptosis, DNA repair, metabolic disruption of the Warburg effect. It goes on and on and on, and you know what? None of them work as well as we want them to. We take them into the clinic, give them to terrified people who have little hope left, and we watch as we provide with them, what? A few months of extra life? Was that what we were shooting for all along, do we grin and shake each others' hands when the results come in? "Another incremental advance! Rock and roll!"
    Of course not. We're disappointed, and we're pissed off. But we don't know enough about cancer (yet) to do better, and cancer turns out to be a very hard condition to treat. It should also be noted that the financial incentives are there to discover something that really does pull people back from the edge of the grave, so you'd think that we money-grubbing, public-deceiving, expense-padding mercenaries might be attracted by that prospect. Apparently not.
    The same goes for Alzheimer's disease. Just how much money has the industry spent over the last quarter of a century on Alzheimer's? I worked on it twenty years ago, and God knows that never came to anything. Look at the steady march, march, march of failure in the clinic - and keep in mind that these failures tend to come late in the game, during Phase III, and if you suggest to anyone in the business that you can run an Alzheimer's Phase III program and bring the whole thing in for $43 million dollars, you'll be invited to stop wasting everyone's time. Bapineuzumab's trials have surely cost several times that, and Pfizer/J&J are still pressing on. And before that you had Elan working on active immunization, which is still going on, and you have Lilly's other antibody, which is still going on, and Genentech's (which is still going on). No one has high hopes for any of these, but we're still burning piles of money to try to find something. And what about the secretase inhibitors? How much time and effort has gone into beta- and gamma-secretase? What did the folks at Lilly think when they took their inhibitor way into Phase III only to find out that it made Alzheimer's slightly worse instead of helping anyone? Didn't they realize that Professors Light and Lexchin were on to them? That they'd seen through the veil and figured out the real strategy of making tiny improvements on the existing drugs that attack the causes of Alzheimer's? What existing drugs to target the causes of Alzheimer are they talking about?...
     
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  2. peggy-sue

    peggy-sue

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    Scotland
    And even tweaking a molecule here and there is not always going to get you anywhere.

    I can remember being given a whole load of compounds to test once. A chemist had spent months and months shoving different metal ions into nitroprusside to see if the variation would reduce blood pressure without forming the cyanide. Only one compound did have a slight BP reduction effect - but so ineffective as to be useless.

    (It wasn't normal to get stuff from chemists from other departments to test like this in a university setting!)
     
  3. Merry

    Merry Senior Member

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    Thanks, waverunner. Eye-opening. Really grim assessment and a reminder of how little anyone knows about so many diseases and how slowly medical science advances.
     
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  4. Waverunner

    Waverunner Senior Member

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    It seems more difficult than I thought. Genetic sequencing is not easy either but at least you have a clear aim. As soon as computers and chips get faster and better it gets easier to achieve this aim. In a few years everyone will get his genome sequenced for a few bucks.

    It's much harder for Alzheimer or CFS. As long as we don't know the exact cause, it will be very hard to find a good treatment. And as long as we don't have proper screening tools for infections or the immune system or other parts, it will be very hard to find a cause. It's a catch-22 somewhat.
     
  5. alex3619

    alex3619 Senior Member

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    These are essentially the same complaints about drug development that I knew back in university. It seems the situation is unchanged in the last decade. Let me add that the internet has made things worse in drug development. Patients in double blinded placebo control trials can contact each other and figure out who is on the drug. When this happens the drug trial can be cancelled. It often does not start up again. This happened with an experimental drug being tested locally while I was at university, although in that case I think the patients had got together in real life and not on the net.

    I keep coming back to a simple point: drug companies attack therapeutic targets, they don't do basic research. Each target is only hypothetical - if its not a good target then the millions spent will be wasted. Researching the physiology of disease is not a drug company's priority - but once its understood they can step in to do clinical trials of potential therapies.

    Bye, Alex
     
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  6. Waverunner

    Waverunner Senior Member

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    Alex, it seems that you are right. As long as the scientific foundation and understanding of diseases is not better, it is very hard to actually cure them.
     

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