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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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In the Pipeline

« And Speaking of Discovering Things. . . | Main | Depressing Figures for Acomplia »

November 15, 2007

Quiz Time!

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Posted by Derek

Do you have what it takes to run a med-chem project? Take this simple test and find out:

1. You have a compound with a suspicious reading in a hERG assay, indicating possible cardiovascular trouble later on. Do you:

A) Brace yourself to scale up compound for dog cardiovascular tox (and brace the budget for paying for it), wondering if the animal group has gone through with that threat to switch to 60-kilo Irish wolfhounds.

B) Brace yourself to start your SAR over, most of the way back from scratch, because your compound doesn’t fit anyone’s hERG model (what are the odds that you could miss them all?) and you have no idea of what to fix first, or

C) Make a pest of yourself by pointing out all the historical compounds, now on the market and not causing trouble, that would have been dumped by running this same assay and taking it this seriously.


2. Your lead compound has come back positive in an Ames test. A re-test was negative. Do you:

A) Brace yourself to fight for your compound’s right to live, even though it will always have the Mark of the Beast on it for having failed that first Ames.

B) Brace yourself to start your SAR over, most of the way back from scratch, because there’s no such thing as an Ames-positive structural model anyway, and you have no idea of what to fix first (and no conviction that anything needs to be fixed at all, except that pesky Mark of the Beast business), or

C) Make a pest of yourself by pointing out that a good percentage of the things on sale at the supermarket wouldn’t pass an Ames test either, especially at your tox doses.


3. You have a compound that you need intravenous blood levels on, but it doesn’t want to dissolve in any of those namby-pamby iv vehicles. Do you:

A) Brace yourself for running the thing in the closest thing that looks like it might work, at the lowest concentration, even though it might not give you any data you can use (hey, at least you can say that you tried).

B) Brace yourself to start your SAR over, adding morpholines, methoxyethyls, all those solubilizing groups that make the structure say “I Used to be a Brick, And I Probably Still Am!”, even though you can’t think of a place to put them without killing your activity, or

C) Make a pest of yourself by arguing for some weirdo vehicle that you pulled out of the literature (Dr. Pepper, hair gel, balsamic vinegar, etc.), which your PK people have never heard of and would rather shave their heads than take the time to validate.

Comments (21) + TrackBacks (0) | Category: Drug Development


COMMENTS

1. milkshake on November 15, 2007 11:45 PM writes...

1: C, while awaiting the results from A
2: the same answer as with 1
3: pro-drug in vain, then B

A compound can be bad or just half-baked. Some assay results should be taken in strides but hints of organ tox or genotoxicity are a serious scare. And you win yourself no favors by dosing patients with a brick-and-cremofor chowder.

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2. weirdo on November 16, 2007 12:09 AM writes...

A
B
B

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3. Hello on November 16, 2007 1:34 AM writes...

A

A (with a bit of C)

C - Why bother with brick-dust in the first place?

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4. ppp on November 16, 2007 4:09 AM writes...

Depends on the therapeutic area:

in Oncology:
C
C
B

in CNS:
C+A
B
B

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5. Dr Baritone on November 16, 2007 5:21 AM writes...

C, C, C for me. Never give up.

balsamic next time.

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6. DrSnowboard on November 16, 2007 5:45 AM writes...

You do A+B+C for all three questions and take whichever answer works.

Though actually, best 3 out of 5 for the Ames and trump with a negative mouse lymphoma..

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7. tom bartlett on November 16, 2007 9:31 AM writes...

I think Dr. Snowboard is closest. To a great extent, what you do depends on your "belief" in the compound; the program; the various assays (Ames, hERG); your ability to makes changes (how forgiving is your SAR--is it THIS compound or nothing?).

"C" answers look the worst on performance reviews.

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8. Ai yi yi on November 16, 2007 10:39 AM writes...

C

C

C

Especially in November, with the year-end goals looming large.

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9. Green Koala on November 16, 2007 11:02 AM writes...

Very accurate and typical examples. Can anyone argue that we have it easy.

I too think Snowboard has it the closest. I personally would have to have more info to answer.

For those of us who have had to deal with such on a regular basis, it does depend on so many other specific and general factors. For example:
- Do you have time/manpower to focus some effort on getting around an issue while the in vivo slots open up.
- Are you trying to answer a yes/no question on that particular compound as a potential clinical candidate or trying to answer a fundamental program or series question.
- How many other issues are there with this compound/series.
- Do you have the collaborative support to follow multiple approaches or is this your shot on goal.
- Do you have support from your management/colleagues. What experiences have they had to help guide you.
- Etc.

One observation from the answers is that most of them are different. No wonder that we could all potentially be working on the same project with similar molecules and end up with very different outcomes, and probably would as history has shown.

GK

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10. Anonymous on November 16, 2007 11:03 AM writes...

For 1 and 3, why weren't you measuring these all along? If you weren't and cost was not the issue, you shouldn't be in a position to run a program anyway. For 2 it's a bigger issue and certainly depends on what you're trying to treat.

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11. CMC guy on November 16, 2007 11:24 AM writes...

All decisions ultimately very dependant on Target (Area/Disease,Acute vs Chronic, Treatment options) and the company culture/atmosphere.

C but do look at additional compounds in HeRG to see if "class" issue then A

A which I think will go to C

B and have Formulations Group/Contractor reach into their bag of tricks to see if reasonable solution possible

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12. Dave H on November 16, 2007 11:40 AM writes...

1 - C
2 - C
3 - C Any drug delivery Guy (or Girl) knows that it can be made to deliver with some USP DMSO and a microneedle transdermal patch. Now if you want a stable patch....

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13. DrSnowboard on November 16, 2007 12:04 PM writes...

To anonymous,
So it's all about managing resources, getting over or under threshold levels in assays set by expert committees? Sounds like we could be replaced by a well-designed spreadsheet, maybe with colourcoding..

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14. devices R us on November 16, 2007 1:23 PM writes...

Dave:
I really like transdermal microneedle patches, but the darn DMSO keeps making them fall off my arm
:)

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15. TNC on November 16, 2007 2:53 PM writes...

Let's see if you have what it takes to be a NFL general manager:

It's draft day and your Hall-of-Fame running back has announced his retirement 2 weeks ago. You are picking tenth in the first round. Do you:

a. trade up and risk the future to draft the running back that everyone thinks will be a surefire winner and has unreal speed and moves?

b. trade down for multiple fourth round picks to stall for time and a few 'value' tailbacks for a cheap "running-by-committee" approach?

c. point out what we really need is an unreal offensive line and it doesn't matter who our tailback is 'cause they make holes your dead grandma could run through?

====

The similarities between drug discovery and player personnel issues in the NFL are remarkable. You have all these predictive tests and past performances of which you're unsure of their predictive validity, value and reproducibility.

Permalink to Comment

16. Hap on November 16, 2007 3:18 PM writes...

On the other hand, you don't have to worry that your best new drug candidate will decide to lead police on a two-mile chase while attempting to drive to the house of a witness in its armed robbery case, or decide to do a little breaking and entering in its time off, or get caught with a bunch of weed and guns in its SUV. Theoretically, the underlying properties of drug candidates are constant, while the properties of people are...not so much.

I like these quizzes, probably because I don't actually work in drug development - when my research reports read like scripts for a black comedy, it's time to polish/sand/rebuild the resume.

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17. DLIB on November 16, 2007 5:48 PM writes...

Great Post.

This illustrates the scariest thing for the future of the pharmaceutical industry. Can anyone pinpoint the ability of the addition of a single type of knowledge that would make the agreement between the medchem guys improve to some degree. I assume that the addition of another type of pertinent info on top of that would increase agreement and on and on... til we had perfect knowledge and there was 100% agreement.

But I bet that none of you could agree as to the first one that would increase the agreement the most. Better SAR with cytochrome enzymes??? Better Herg channel assays?? -- a better assay for QT than herg??? better screens for mutagenicity???

I think the statement is obvious but the post is a great illustration of the point and has got to make the business guys fret.

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18. Great Molecular Crapshoot on November 17, 2007 2:51 AM writes...

This quiz is an excellent idea although I'd have preferred if there had been the D option of project closure for each question.

For scenario 1, I'd be considering option A if the compound was something we were looking to take forward. These days the FDA is going to want to see that sort of data regardless of hERG assay results. However I'd want to take a look at whether the hERG activity was observed for several compounds in the series. I'd also be looking at the IC50 (and concentration response) in the hERG assay and asking if it was binding of functional. If the IC50 is 25 micromolar and it's only seen for a couple of the more lipophilic representatives of the series then C. However for a compound that you're trying to take forward, it's not your colleagues that you have to convince but the FDA.

Question 2: A, provided that we can firm up on the Ames because we're not going to be able to take an Ames+ compound forward regardless of the arguments of the C-brigade. If Ames+ appears to be related to the series, then B becomes the favored option given that the D-option is not available.

Question 3: B because I would not be confident that we can formulate your way out of an in vivo solubility problem. With IV agents, keeping the compound in solution is not just for efficacy; precipitation from plasma can be catastrophic. Note that I'm assuming this is meant to be an IV agent and we're not doing this as part of a target validation exercise.

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19. Kay on November 17, 2007 3:29 PM writes...

D: Make a few folks redundant; sit back; wait for a small company to get something to the clinic; pounce.

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20. Barbara on November 19, 2007 10:13 AM writes...

Love the quiz.

1. Push for C, while bracing for the inevitable A.
2. Ames, Schmames --> C.
3. On planet Earth, I think you're stuck with B.

Permalink to Comment

21. Dr Baritone on November 20, 2007 9:22 AM writes...

Have got back to this, especially since my good friend Dr Snowboard's comments.
In my experience
1. We start out with C and do A. nobody listens, its flavour of the month,.....and watch your free fraction. Have you seen hERG pharmacophores!....And then theres phospholipidosis!
2. We start out with C, we get to A pretty quickly, then they start Ames testing our intermediates, so at that point we go to B and hope we have an alternative pretty quickly. at this point the company decides that genotox testing needs to be "restructured"!
3. If your struggling for solublity for an i.v. dose having done all the simple stuff. Kiss it goodbye. There's better stuff to work on.

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