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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 31, 2005

Five Questions

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Posted by Derek

Here are a few more of those questions that come up during drug research. Readers with experience in the industry may have had to deal with these very ones, and will at least recognize them as the sort of head-scratchers that every project has to deal with. Most of them, as usual, have more than one right answer, depending on the circumstances. So. . .

1. You have good compounds as measured in an enzyme or receptor assay in vitro, but they do nothing what's supposed to be the relevant cell assay. Usually, the assumption is that they have trouble getting into the cells. But then you try them into another cell line that's not necessarily supposed to respond to this target, and they suddenly work just fine. Now what?

2. You have limited chemistry manpower on a project. You're all using a common intermediate, so you put some effort into making a big stock of it for everyone to use. But then a patent application publishes that comes uncomfortably close to what you're working on. The next application from those guys might pull the whole chemical series out from under you. How do you deploy your people to deal with this one?

3. Your team is cranking away, making compounds that are more and more potent in the primary assay against your protein target. The new ones are getting more and more selective against the potential side targets, too, so what's not to like? Well, the compounds are also getting bigger and greasier, and their blood levels are getting worse and worse when dosed in the animal models. When do you call a halt?

4. Several lines of evidence are beginning to make you think that your compounds are doing the right things for the wrong reasons. You're getting the effects you want in vivo, but your initial assays don't correlate with the animal data (or with each other) very well. Do you care, and if so, how much?

5. Your project is narrowing down to two potential candidates. The first one has fair to mediocre potency and selectivity in the assays, but wonderful blood levels. The second is as potent and selective as all get out, but has marginal blood levels and requires ugly dosing vehicles. Which one do you pick, and how do you decide between them?

Comments (10) + TrackBacks (0) | Category: Drug Development


COMMENTS

1. Jim Harris on November 1, 2005 6:24 AM writes...

Animal PK is not predictive of human PK because the enzymes that do the sorting and chopping are different and because humans are outbred and, hence, much more variable than those creatures in the vivarium. As a result, #5 is an easy choice once you gulp down the facts above.

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2. Derek Lowe on November 1, 2005 7:06 AM writes...

Ah, but we run our compounds past human metabolic enzyme preps as well as rodent (and dog) ones) whenever possible.

Compounds with good animal PK can (and do) come up short in people, although that's still a nasty surprise. But a compound with awful animal blood levels has much better than even odds of having trouble in humans, too.

You're right that human PK is pretty variable, though. That's a whole separate headache. . .

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3. Oldchemist on November 1, 2005 7:35 AM writes...

I tell the youngsters I mentor that it's exactly these questions that are the "meat" of running a project. If getting a drug were easy, we'd all be out of a job.

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4. Erich Schwarz on November 1, 2005 7:47 AM writes...

"Scientific" wild-eyed guesses, from a pure academic biologist:

1. I don't know. Simplest answer: just go with the second cell line. Longer answer: try curing the first cell line to get an idea of whether this is really a blocked import problem. One way to do that would be to add some chemical agent such as liposomes or very dilute organic solvents such as ethanol or DMSO. Another, weird to do this: make a fusion of the two cell lines and see if the ability of the cell line to respond is a dominant or recessive trait.

2. Deploy 0-1 people to work on an alternative synthesis. I don't know how it works in the Real World, but in academia, if you worry too much about almost being scooped, you'll go insane and yet not prevent anything bad. Also, this is really only an issue if you actually get a drug candiate from your current stock that looks genuinely promising. I get the impression that such an event is itself rare.

3. Impossible to answer without numbers. It's got to be a quantitative trade-off: is this drug getting specific more slowly than it's getting unimportable? That's quantitative.

4. I care but not in the obvious way. I don't care at all from the perspective of whether to go ahead with the drug: humans have >25K proteins and we truly do not know how most drugs are affecting most of them (there's serious evidence from C. elegans that a major effect of Prozac isn't on serotonin uptake at all, for instance, yet the drug does work!). I do care in the sense that I would like to figure out what the real target is so that I can start to do more intelligent future drug hunts, and so I can generally have an idea how to most intelligently interpret my lab results.

5. Go with the first drug. Specificity of drugs may be overrated (much as I, an academic molecular biologist turned bioinformatician, hate to think that); meanwhile, getting the drug into the person easily is pretty important for any drug that will be used by normal people.

(I'm going to be deeply amused if even half of these answers are even plausibly correct...)

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5. Derek Lowe on November 1, 2005 9:25 AM writes...

Erich S., I'll say right off that I think your answer to #5 is the same as mine, not that that necessarily makes it the right one. That question needs a tie-breaker. I'd try to take both compounds as far along as I could in animal and tox models, and hope that rat tox or dog PK would decide the issue. But I'm biased toward good oral blood levels, too.

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6. Mark McPhee on November 1, 2005 10:06 AM writes...

These all sound like great qualifying questions for identifying real "drug hunters" interested in joining your firm, for example, at the Senior Scientist level or above.

I certainly have my own set of questions for bioanalytical and process folks who aspire to join one of my client firms.

I just wish we could introduce these types of real-world conundrums in a didactic fashion to aspiring pharma scientists while in graduate school.

For example, I dont think it would be too hard, given appropriate case examples, to get most synthesis grad students to wrap their minds around the operational cans and cannots of synthesis on the kilo scale.

You have written well, Derek, about the roles and divide between industry and academe. My point is that good scientific reasoning skills can still be the end result of grad school while simultaneously preparing students for the real world in industry.

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7. Jim on November 1, 2005 11:56 AM writes...

Regarding #5, I tend to agree with the first post in that I don't put a lot of faith in animal PK (in terms of its predictive validity). However, Derek your statement about trying to get both compounds as far along into tox studies is perhaps the most prudent. It's still a whole lot cheaper to run these studies in monkeys that to do any phase of clinical trials....

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8. Jim Harris on November 1, 2005 12:27 PM writes...

Taking all possibilities forward is a fantastic strategy if you can afford it. Animal PK and human test tube and culture methods are dead money (see Tommy Andersson of AstraZeneca, Clin. Pharmacokinet. 2003 for an introduction; I will provide further references if asked).

Human screening in northern Europe (i.e. parallel microdosing) and maybe (maybe) transgenic animals are the only hope going forward.

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9. milo on November 2, 2005 11:37 AM writes...

Wow... never really thought of these as being potential issues. Since I am looking for something to do after my postdoc, I really appreciate seeing potential "interview discussion points" :-)

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10. Giagan on November 2, 2005 1:11 PM writes...

Milo,
Trained purely in synthetic organic chemistry, I am certainly glad that none of these issues came up for discussion on my interviews! Actually, the interviewers were happy to talk about synthesis and in reply to the concerns I expressed about knowing little med chem, they said that they would teach it to me on the job. However, if you're a regular reader of this web site, then I can tell you that you've got a leg up on all the other candidates. I wish I had found the site a year or two earlier!

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