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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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October 29, 2009

Four Med-Chem Questions

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Posted by Derek

Here are a few more of those questions that medicinal chemists have to deal with from time to time. Most of these have no definitive answers (which is why they keep coming up!)

1. You're making a compound that looks to be important in the project - maybe even the clinical candidate, if things go right. But there's a step in the synthesis which - while it does work - is clearly not something that's going to scale up too well. You need more compound right now, and you can push things through. But you're eventually going to have to ditch that step (unless this compound gets overtaken by another one), so. . .when's the right time to worry about that?

2. Your compound series is in a pretty crowded patent landscape. In fact, another application has just published that really looks to be breathing down your neck. Of course, that means the work in it was done a year and a half ago (or more). Can you assume that Company X has followed the same course that you have, and has already investigated the series you're working on? Should you drop them, or go in in the chances that six months from now another application will drop that covers you like a tarp?

3. You're finally writing up one of your old projects for publication. But it's been a while, and the details of what happened are not as sharp as they were when thing were going on. What's more, on looking the work over, you realize that there are some obvious gaps in it, stuff that didn't look that way at the time, but sure does so now. You can write things up to make it look more coherent, but only by rearranging the way it really happened. Where do you draw the line?

4. Your lead compound is ready to go into toxicology testing, the last big step before declaring victory and naming it as the development candidate. Trouble is, there's something funny about it in rats. They just don't get the blood levels that mice and dogs do, and your tox people would really, really rather run the tox study in rats (since that's the standard, and what they have the most comparison data for). Update: I mistakenly switched rodents mentally this morning on the train, now they're switched back to what they should be). You can get the blood levels up to where they need to be - but only by using a dosing vehicle that might have problems of its own, and that the toxicologists haven't had much experience with either. What to do?

Comments (19) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. Mark on October 29, 2009 8:43 AM writes...

Lately, the answer to question #1 for a lot of companies is "as late as humanly possible". Spending $1 million on improving the chemistry of a candidate that has a 90% chance of dying gets really expensive in the long run.

Then again, delaying development of a new drug because the chemistry sucks can get really expensive too.


Mark

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2. You're Pfizered on October 29, 2009 8:58 AM writes...

1-It all depends. For preliminary in-vivo work and POC studies (1-5g of material), I'd muscle through and get the compound out the door and see if it's even worth worrying about. Anything above this amount usually would get handed off to the process folks, who would probably want to re-work the chemistry in many of the steps anyway, especially ones that require chromatography.

In a perfect world you've got process folks either coming to your group/project meetings early enough to start to think about potential problematic steps and potential work-arounds.

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3. Vasili on October 29, 2009 9:11 AM writes...

1. It depends on the responsabilities and accountabilities. If you are accountable for making only that small quantity of material in the shortest amount of time possible just go ahead. Now, if the compounds goes further and you will be accountable for preparing larger batchs I would care now about improving the chemistry.
It can be dependable on the company structure, some companies have medchem and then process others have some group in the middle that cares about the chemistry 'couse they must prepare more than, let's say 100g.

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4. Vasili on October 29, 2009 9:15 AM writes...

1. It depends on the responsabilities and accountabilities. If you are accountable for making only that small quantity of material in the shortest amount of time possible just go ahead. Now, if the compounds goes further and you will be accountable for preparing larger batchs I would care now about improving the chemistry.
It can be dependable on the company structure, some companies have medchem and then process others have some group in the middle that cares about the chemistry 'couse they must prepare more than, let's say 100g.

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5. HelicalZz on October 29, 2009 9:31 AM writes...

What you don't do is answer any of these questions, which don't have correct answers, in your own mental vacuum. Communicate the risks as widely as appropriate and move forward as best you can.

If the decision is your responsibility, make it, record the what and why, and let it go. It's the prolonged handwringing over issues like these that is more the problem than the problem itself.

Zz

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6. a med chemist on October 29, 2009 9:51 AM writes...

1) While waiting for 2 week rat PK data to come back from that oh-so-pleasant scale up you just pushed though. At this point you have 2 things on your side - management is now tapping thier fingers for the biology not your compounds and you still remember how bad the synthesis actually was.

3) Id rather fill the gaps now than rearrange what happened. I just think of how many times reading papers I wish the authors added the mistakes they made - and how they went on to fix them. Yeah it doesn't look as pretty but its honest and people can learn from it.

4) Gut feeling, I'd probably use the rats. The real question here is whats mimicing the human liability better, the rat/dog or the mouse? (Is the problem just isolated to mouse or are rats/dogs able to get blood levels becuase they lack/have something present/absent in human/mouse?). If its limited to mouse it doesn't make much sense to get all this data on a system where the vehicle may be causing problems in addition to the compound so despite all the comparison data you have the whole thing might be flawed and thrown out anyway. Especially when the toxicologists haven't had much experience with it as it would be harder for them to say wether its the vehicle or the compund causing problems.

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7. Philip on October 29, 2009 10:05 AM writes...

1. You should push through more material but it seems to me that a good organic chemist should worry about the quality of a route all the time, even years after the project is over.

2. Tough call. Depends on how close. Me-too makes money often.

3. You draw the line at the truth.

4. Tough call. Mice are a lot cheaper than rats or dogs. Call a meeting to spread the responsibility for any decision.

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8. MedChem on October 29, 2009 10:05 AM writes...

Derek,

My understanding is rat is the standard species for tox studies. Not so at your company?

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9. KinaseNerd on October 29, 2009 10:11 AM writes...

1.) I stick to my synthetic route until it will be finally decided that it is really going to be a clinical candidate (i.a. tox results are looking good).

2.) Get your hands on the US or EP priority document and compare the example list to the WO document: Any additional examples in the WO -> They have been actively working on it over the last 18 months (or 12 thereof). You should really be worried. No additions in the WO -> They may have already found there candidate or are not really intested in this series. Don't worry too much. Think about all your "obvious" ideas sitting in your drawers which will never be realized due to capacity limits. Your lead series may be close to what they have published but there is probably not only one next "obvious" series.

3.) That's simple: Stop writing publications!

4.) What is wrong with rats or dogs as tox animals (aside from the larger amount of cmpd needed)? Check your metabolite profile with hepatocytes from the different species. You should chose your tox species based on similarity of the metabolite profile with human hepatocytes. Don't go for fancy vehicles if your don't have to.

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10. CMCguy on October 29, 2009 10:20 AM writes...

#1 although would be extremely nice sometimes if they did more upfront medchemists should not spend too much time and effort on what is needed for scale-up.

#2 Tough one but would see where you can take it and hope indeed Company X did not scoop you. In parallel would explore alternates

#3 Most talks end up condensed versions of success that seem artificial, since people in lab know never a straight line. I often learn more from gaps/failures even if came from retrospective analysis. Write the story and admit could have done differently. My guess is most PhD dissertations are written as "good stories" rather than real telling and could be both.

#4 Occasional problem encountered although preferred/creates issues the dosing vehicle for animal studies does not have to be same formulation as humans. Most folks I know would favor human formulation in Rats etc but in the end out of medchemist hands.

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11. Darwin on October 29, 2009 10:23 AM writes...

Answers to all questions are inherently dependent on R&D funding via VC, private or publicly held company.

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12. Vader on October 29, 2009 10:34 AM writes...

"Your lead compound is ready to go into toxicology testing..."

I'd avoid compounds containing lead no matter how promising they look in vitro.

------------------------------------------------->

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13. Jose on October 29, 2009 10:53 AM writes...

Rats are dicey as primary tox species- they've evolved lots of jazzed up enzymes to deal with living in toxic environments.... not wholly applicable to lab strains, but still a serious issue.

Answers to 1-4: how truthfully do you want to "meet" your year end goals and get a bonus?

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14. Hap on October 29, 2009 11:02 AM writes...

But my thallium compound works great as an antiproliferative in vitro. You mean it's probably not going to make it to Phase II? Damn.

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15. milkshake on October 29, 2009 11:18 AM writes...

If there is some extra time, even on weekend, I actually like to re-optimize crappy methodology a bit, try alternate ordering of transformations or even a new route. The thing is, even if the projects dies later on you have learned interesting and possibly useful tricks, and your improved route may allow preparation of a substitution pattern that could not be touched by the previous (unsatisfactory) way. You earn the bragging rights and an interesting tidbit for a future job presentation. And you won't have to submit a crappy procedure for publication (or pass it on your labmate) - a procedure which you know will be hard for others to reproduce.

You see, the most bosses have tendency to rush things to meet the (unrealistic) progress report projections and when you spend two weeks optimizing important reaction step they complain about you playing and wasting time instead of cranking out analogs. One ought to resist this pressure and possibly look for a boss/research group that is more reasonable.

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16. JC on October 29, 2009 11:24 AM writes...

1. Never.
2. No. File a ton of prophetic examples & keep on trucking.
3. You don’t. Anyone who would object either doesn’t work there now or does & is more than adequately cowed.
4. Vehicle control.

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17. Tok on October 29, 2009 11:43 AM writes...

1. Don't bother. Give your Chinese replacement something to do when you get laid off.

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18. researchfella on October 29, 2009 8:27 PM writes...

#3 is easy. You can write a good article that truthfully describes the data. You don't need to tell a story based on the sequence of events.

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19. E on October 30, 2009 4:06 AM writes...

Speaking as a toxicologist... maybe the tox group can be convinced to change rodents? Although we whine and whinge about not having historical control data, no one's ever done studies in species X, etc etc, we can be talked around if there's sense to the argument. We're going to wish there was some other company that had put a compound into development using a non-standard species first, of course, but we may decide to take a deep breath and jump in anyway.

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