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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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September 14, 2010

How Much Compound?

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Posted by Derek

Here's a question for those of you out in the industry: how much compound do you make, when you make a new one? Sometimes this question is equivalent to asking "How little will they let you get away with?" Different organizations have different requirements, on paper and for real, as to what that amount is. Five mg? Ten?

I've worked with people who kept coding these little 1.5mg amounts on most of their compounds, but I only do that if I'm desperate. That's really only going to do the immediate project any good, and not much, at that, if you want to do anything beyond the first in vitro assays. You'd like to have something living in the screening files so it can perhaps do some good later on. I try to aim for 10 to 20mg of compound, myself, although I don't always make it. And you?

Comments (32) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. processchemist on September 14, 2010 1:21 PM writes...

Few years ago at my shop landed a medicinal chemistry project where other contractors performed poorly. Few (about 20) analogs to crunch, a synthesis to be reinvented. The customer was using the compounds for in vivo SAR (rats) so the minimal amount required was 500 mg.

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2. You're Pfizered on September 14, 2010 1:37 PM writes...

Depends on the maturity of the project, really.

Typically, I shoot for anywhere between 25-50mg if the chemistry is amenable (purification, really). Covers a fair amount of preliminary testing.

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3. anchor on September 14, 2010 2:22 PM writes...

#2 is correct and typically we make 20-25 mg. 2-3 mg for assay, 7-9 mg for PK, 2 mg for other assays (to get preliminary results), 5 mg for the sample collection and the rest just in case.

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4. CRH on September 14, 2010 2:42 PM writes...

My previous company had the requirement that 150 mg had to be made for every compound. The reason being there would not be a need for re-synthesis until a much later date, and most of the work would be done on the same batch. The requirement for library compounds was much less (30 mg); and thus everyone was performing library synthesis even if it was only a 1 X 2 library.

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5. David P on September 14, 2010 3:18 PM writes...

For my current project we need 3-5 mg for initial submission. I usually aim for 20-30 mg and then if I miss then I can still at least make the submission. Of course I am doing more basic research so worrying about PK and the like (and the compound to submit for those) is not really relevant. Still, it is nice to have a little more on hand in case some more experiments are required, even if it is just to re-test.

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6. Arnold on September 14, 2010 3:58 PM writes...

10 mg for biochem assays, in vitro DMPK assays and solid reserve.

30 mg all of the above plus rat PK.

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7. Iridium on September 14, 2010 4:04 PM writes...

My current company doesn't have any requirements on quantity beyond whether I can get an accurate weight on the sample, so >1 mg. However, I always try to shoot for more. If the synthetic route is short and/or easy I try to prepare 100+ mg because we run numerous assays here. However, 20-30 mg would get us by for quite a while in reality.

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8. cynical1 on September 14, 2010 4:29 PM writes...

I know I'm dating myself but when I first started in the industry, 25 years ago, I had to make two grams of every compound. Period. If I wound up with 1.9 grams, I had to resynthesize. I'm pretty sure that there is still over 1.9 grams of all the compounds I made still in their compound stores. Nowadays, I make 20-25 mg mostly because I am purifying everything by RP-HPLC and I hate being a human fraction collector for multiple injections on my semi-prep. (We are a tiny start up - no frills or fraction collector.)

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9. Owen Jacobson on September 14, 2010 4:57 PM writes...

So, how far down a project do you need to be before you can estimate how much of each raw material you're going to need to make ~10-20 mg of a compound? Given the complexity of most (but by no means all) drug-like compounds, I would expect the synthesis to require an unpredictable number of steps, some of which may take some time before yields start turning predictable...

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10. MedChem on September 14, 2010 5:59 PM writes...

A requirement of 2 g is INSANE! Even 100 mg is excessive for early to mid stage programs. It only encourages people to make amides and stay away from worthy and difficult to make cmpds.

Another clueless uppper management directive that hampers innovation.

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11. alig on September 14, 2010 9:01 PM writes...

I have my chemists in Chindia target 25 mg.

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12. Jose on September 14, 2010 9:20 PM writes...

Medchem... " when I first started in the industry, 25 years ago..."

I think the point cynical1 is making is that PK/PD and other assays have gotten 100 times better since then; nothing at all to do with "clueless uppper management."

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13. London Chemist on September 15, 2010 2:29 AM writes...

"clueless upper management"

At my previous company, we were told to absolutely not make more than 10mg as it was a waste of intermediate to do otherwise. We said it wasn't enough and were labelled as awkward and behind the times. Then we hit a good series and needed to progress to in vivo e-phys expts for which we needed more than 10 mgs, so had to re-prep. "Why weren't we making enough first time around?" asked management. "We should have anticipated this situation" and were labelled as bad planners....

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14. Scoop on September 15, 2010 4:41 AM writes...

I worked on a project where the minimum submission was 50mg. Just because. And because on-one thought to question it. Turns out the argument went along the lines of "We need 2mg for assay, but to be accurate, it'd better be 5-10 mg we ask for, and as chemists always underdeliver, we'd better ask for 20 mg. Tell you what, make that 50 mg to be on the safe side."

Did it make things run faster in the long run? No. Because we'd spend weeks making 50mg of stuff which proved to be inactive, rather than a quick synthesis of multiple analogues at 5mg each, to get through binding, functional and limited in vivo assays to find out it wasn't worth making any more....

Granted, requirements vary project to project, but getting realistic (and minimalistic) requirements from the assay group makes a dramatic difference in compound submission.

Starting a new lab from scratch has enabled us to look at this in detail, and eliminate a lot of the wasteful steps along the way, particularly in the serial dilutions of compounds. (You know the ones, those that use 20uL of stock solution per assay but then discard the vast majority of it post dilution and only use a fraction in the assay...) Liquid handling, and the inherrent attrition of compound stocks seems to me to be the key reason behind >5mg submission requsts, not the absolute requirement of how much compound is actually needed to evaluate biological activity.

Problem with this is that you need accurate dispensing at low volume and this is not trivial. Acoustic dispensing helps dramatically but is still not perfect. However, coupled with prep HPLC for purification, we can now realistically salvage material from reactions we'd previously discard as being too low yielding and get a mg or so into solution for screening, which gets us through primary and functional screens (upwards of 5-10 assays) and still leaves enough for evaluation in a phenotypic cell assay. (And usually even some outline in vitro DMPK)

We then only re-make compounds with a valid reason for doing so - saving materials, time and cost and a lot of frustration and hassle for the chemists......

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15. GladToMoveToProcess on September 15, 2010 6:34 AM writes...

Back in the 80s, we also had to submit 2 grams. That would be enough for the in vitro tissue assays (rarely could we do even primitive biochemistry), and, if the compound showed even marginal promise, enough for some in vivo tests (dogs! No good smaller animal models). Part of the reason I was glad to move - it was more satisfying to spend a lot of effort on something that was beyond "marginal promise." Of course, a 2 gram first prep usually meant that our kilo lab and process groups had reasonable syntheses as starting points....

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16. JB on September 15, 2010 8:08 AM writes...

I run a CM and an HTS group- for inclusion in the HTS deck the minimum is 1mg. Using a 500MW for easy math, that gives you ~200 uL of a 10 mM pinning stock. That will make you a set of HTS stock plates for 6-12 months plus have some available for cherry picking / dose curves of primary hits. You can do a whole lot (dozens) of primary assays from 1 mg.
The libraries we're making in-house usually generate 5-10 mg, when we have that much we use 1 mg for a DMSO mother tube and keep the rest dry, and we keep all the intermediates around for quick scale-up of any given compound.
Submission to the NIH network HTS library requires 6 umol, so ~3 mg. If it's for distribution as an NIH probe compound they require 50 mg.

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17. LeeH on September 15, 2010 8:34 AM writes...

At my previous company the requirement was 50mg, then it changed to 25mg. The amount purchased for the HTS deck started at 5mg, then went to 17.5mg, then went to 11mg, according to the prevailing opinion as to how much might be necessary for follow-up in-vitro assays.

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18. InfMP on September 15, 2010 8:39 AM writes...

I usually submitted 0.5mg-0.8mg for assay.

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19. Great Molecular Crapshoot on September 15, 2010 9:44 AM writes...

Always by weight and never by moles?

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20. Lu on September 15, 2010 10:08 AM writes...

Hi Derek,

I wonder why the quantities are so low. For us biochemists a 20 mg sample of, say, protein is A LOT. Things get expensive no matter which route one uses to make peptide - synthesis, cell expression or extraction from some biological material.

But why is it so bad for organic chemists? What is the most limiting factor? Is it cost of materials, purification issues or something else?

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21. Anonymous on September 15, 2010 10:24 AM writes...

@ Lu:

It just takes us just enormous efforts to reach sophisticated, late stage compounds. You may start from 10 grams of starting material, but after seven steps, you have seriously reduced that amount. Also, you try to not always use all the compound you have for your first reaction, to avoid going through the previous three steps again after failure. And there is plenty of failure...

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22. okemist on September 15, 2010 10:28 AM writes...

Aw you medchemmers are sooo adorabul. I don't think I have ever made 50mg of a compound, ha that an NMR sample if I don't weigh it.

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23. MedChem on September 15, 2010 10:57 AM writes...

The majority of early stage cmpds you know before making them that they're NOT going to go in vivo. So why make that much. It's a complete waste of time and resources. Again this is part of the one-size-fit-all, let's-make-them-because-we-can, we-gott-make-the-numbers mentality that's so prevailing.

Now later stages are a complete different matter where you know you need to make more for more studies.

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24. Daniel Levy on September 15, 2010 1:19 PM writes...

Lots of great comments on this post. What I noticed is that most of these posts reflect personal goals regarding how much of a compound to make. In general, the effort to prepare 10 mg is not significantly different than the effort required to prepare 100 mg. Targeting towards larger quantities allows for additional screening of interesting structures from the same parent lot. Additionally, it reduces needs for resynthesis of compounds that eventually do not make the cut. While recognizing that chemistry does not always cooperate, I generally ask my team members to target at least 100 mg of each compound destined for submission.

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25. Nick K on September 15, 2010 2:56 PM writes...

Interesting to see how things have moved on since my time in the trenches twenty years ago. We aimed to make at least 1g of final, testable compound, with an absolute minimum of 300mg needed for registration.

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26. weirdo on September 15, 2010 9:37 PM writes...

It is quite revealing to read some of these comments, particularly the ones that profess that anyone who makes more than a mg or two is wasteful or stuck in the past (I'm looking at you #23). By far the best leads for my programs have come from internally synthesized molecules from old projects (as opposed to purchased molecules or ripping off others). Thus, the "1 mg is enough for my screening assay" attitude is just as bad as the "next quarter's numbers are more important than long-term planning" attitude of MBA's and CEO's that are so often denigrated by commenters on this blog.

Which tells me that many of the whiners wouldn't do anything different if they were put in a strategic management position.

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27. Tryin4goodcmpds on September 15, 2010 10:49 PM writes...

Great post..... I've been on both sides of this one before. Reality is that putting 20-50mg in the collection is a good thing long, medium and short term and so is a great goal. But if you get 1 mg, well you can still learn from that so you code it. Those that see the big picture will shoot for the 20-50. Those that evaluate progress will see the value in the 1mg submissions. Agood balance keeps you out of trouble and the program moving. The problem comes when the metrics man is bell curving performance evaluations and decides to quantitate the things that don't matter. When scientists start to care about performance metrics innovation is the corner that gets cut.

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28. MoD on September 15, 2010 10:57 PM writes...

Kudos to #24 and #26.

We target 100mg quantities. Therefore, if the chemistry/purification does not work out and you end up with 50 mg, then we are still in good shape to 1) get our primary data, 2) secondary cell assay data, 3) collect DMPK data, and 4) fuel the compound collection.

Aiming for 1-10 mg is BS. High numbers of compounds with high throughput purification is BS. Why run an HPLC when you can run a traditional column and get it faster? This type of behavior, attitude, and love of metrics is killing this industry. It is contributing to the disappearance of the "art" of organic chemistry in the pharmaceutical industry. At the same time it feeds the tendency to outsource the same BS "analoging process" to India and China. Good luck with your project.

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29. JB on September 15, 2010 11:35 PM writes...

Why on earth would you want to run an entire discovery project from one batch? You're setting yourself up to be fooled by an artifact- even if I had 10 g I'd still want another batch synthesized to confirm across the assays.

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30. DrSnowboard on September 16, 2010 6:08 AM writes...

I agree with #24 & #26 but then I'm lead optimisation. If you can get primary, secondary assays + an inital DMPK read from your first 50mg, why wouldn't you make more than 10mg, just because its the scale you like? If you do the maths, it takes some very expensive reagents before your time isn't the major cost in preparing a new compound. Start on a larger scale, dumbass. If you have to remake, you just doubled the time and the cost. And bled momentum away from your project. On the other end, how many of us have got an HTS hit and then found there's not enough left to move on with, but the original sample was a bit grubby...And the remake doesn't repeat.

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31. MedChem on September 16, 2010 11:48 AM writes...

26. weirdo

When did I say 1 mg is good enough? The person in my team who consistently submitted 1 mg got a serious talk-to. I ask my team to shoot for 30-50 mg if at all possible. But we hardly ever do any amide couplings. We take what we get. The most important thing I want my team to focus on is quality of design and not some numbers to meet.

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32. Norepi on September 22, 2010 3:48 PM writes...

We always end up doing more assays post-facto, so I generally want between 50-100 mg of a new compound. Something will occasionally compel me to make more though...

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