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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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March 18, 2010

Make Your Compound Go Away

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Posted by Derek

I'm not sure that the term will catch on, but this new paper proposes "antedrug" to describe a compound that's deliberately designed to be cleaved quickly to something inactive. I see where they're coming from - reverse of "prodrug" - but in spoken English it's too close to "anti-drug". Hasn't someone come up with this concept before? Perhaps they didn't bother to name it. . .

UpdateSomeone at AZ sends along this earlier reference to "antedrug".

Comments (23) + TrackBacks (0) | Category: Pharmacokinetics


COMMENTS

1. Chris on March 18, 2010 1:00 PM writes...

How about readily 'cleaved to inactive metabolites'?

Permalink to Comment

2. barry on March 18, 2010 1:04 PM writes...

lots of biological signals that are meant to be limited in time or space (thromboxanes, catecholamines...) are chemically fragile. This is just biomimesis.

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3. Anonymous on March 18, 2010 1:23 PM writes...

Yes, the concept has been used before - remifentanil is an opioid which is broken down rapidly by plasma esterases, and has been around for a decade or so.

http://en.wikipedia.org/wiki/Remifentanil

Permalink to Comment

4. Will on March 18, 2010 1:27 PM writes...

I think it's an especially poor choice for a name, as "ante" literally translates to "before," an antedrug sound synonymous with prodrug - I would prefer "brevidrug" (short [lived] drug)

There I was thinking middle school Latin never did anything for me!

Permalink to Comment

5. Will on March 18, 2010 1:30 PM writes...

forgot to mention that a lot of topical steroids are designed to work this way, ie, active on the cells to which they are directly administeed, but then cleaved to an inert compound once they hit the blood in order to keep systemic steroid levels down

Permalink to Comment

6. Ed on March 18, 2010 1:38 PM writes...

In order to receive the AstraZeneca Meritorious Leadership Award 2010 (with Scienctific Communication Excellence Honours) new key buzzwords had to be invented.

All very helpful, those awards, in padding out the resume/CV now that your site has been closed. Coming from biotech, the amount of such totally meaningless bullshit at Big Pharma never ceases to amaze me.

Permalink to Comment

7. Anonymous on March 18, 2010 1:58 PM writes...

Note to Kurimoto & company: Look up remifentanyl, a short acting anesthetic with a 4 min. half life. It's got two methyl esters hanging off a fentanyl core. The "antedrug" drug approach is far from novel nor terribly difficult to achieve. It's usually the converse that is the challenge for us.

Permalink to Comment

8. Anonymous on March 18, 2010 2:00 PM writes...

.........sorry that's spelled remifentanil

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9. anon on March 18, 2010 2:04 PM writes...

I have seen these refered to as soft drugs.

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10. bbooooooya on March 18, 2010 2:05 PM writes...

Don't most biotechs make anti-drugs?

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11. milkshake on March 18, 2010 2:39 PM writes...

yep, putting a soft spot into the molecule on purpose, to cut the halflife or to avoid lingering active metabolites. Everyone has been doing it - for decades already; these dudes are just putting their own dogtag on the concept.

Permalink to Comment

12. Rich Apodaca on March 18, 2010 2:56 PM writes...

I remember a seminar given by a member of the team who developed Celecoxib (back in the glory days when layoffs only happened in high-tech and manufacturing). He made the point that although methylsulfones worked as substituents, the resulting compounds had unacceptably long half-lives.

The sulfonamide was deliberately chosen to create compounds that were metabolized more rapidly.

Sometimes you can have too much of a good thing.

Permalink to Comment

13. Maks on March 18, 2010 3:12 PM writes...

What about Budesonide?
http://en.wikipedia.org/wiki/Budesonide

I remember that they put the ketal in order to get it cleaved quickly and prevent systemic side effect.

Permalink to Comment

14. Kerry on March 18, 2010 3:53 PM writes...

At Searle in the '80s they were called "soft drugs".

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15. ChemPharm on March 18, 2010 3:55 PM writes...

Esmolol is an exmaple. It is called "Soft Drug"

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16. David P on March 18, 2010 4:37 PM writes...

Makes sense, we don't want to give people hard drugs.

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17. Anon on March 18, 2010 5:04 PM writes...

Soft drug, used for many years.

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18. Jonadab the Unsightly One on March 18, 2010 8:22 PM writes...

I agree with Will. To me, "antedrug" would, if it were a word, mean the same thing (or very close to the same thing) as "prodrug". Replacing a Greek preposition with a Latin one that means the same thing seldom alters the meaning of the resulting word very much.

If the idea is that it quickly moves away from being a drug, I'd have probably reached for apo- (away from) for the prefix, or perhaps meta- (after) or ek- (out of), but brevi- would work too, and probably makes more sense to people who don't know dead languages. And yeah, "soft drug" is just as fast to say or type, so.

Permalink to Comment

19. A Nonny Mouse on March 19, 2010 6:14 AM writes...

The neuromuscular blockers of the atracurium series (mivacurium, doxacurium) were designed to be metabolised, but by different modes, so that once the infusion was stopped the patient quickly recovered without intervention.

Permalink to Comment

20. LondonChemist on March 19, 2010 7:17 AM writes...

Something very similar has been common practice for inhaled and topical drugs for some time--stick a metabolite handle so that the drug is deactivated in first pass.
Seems a case of reinventing the wheel and giving it a funky new name......

Permalink to Comment

21. petros on March 19, 2010 7:44 AM writes...

Been common usage in disucussing inhaled steroids for ca. 20 years!

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22. molecular architect on March 19, 2010 1:02 PM writes...

#11 Milkshake,

Kind of reminds me of when Still et al published their JOC paper on "Flash chromatography". People had been using air and Nitrogen lines to accelerate silica gel chromatography for decades. Amazingly, that paper was one of the most cited papers in history (as of the mid- to late-90s).

I remember an incident as an undergrad, years before Still's paper, where I saw a fellow work-study technician put his mouth on the top of an aqueous ion exchange resin blowing into it to try and speed up the column. He had a date he didn't want to miss!

Permalink to Comment

23. molecular architect on March 19, 2010 1:05 PM writes...

Actually, SHE had a date - but I was afraid of some of the comments this info might elicit!

Permalink to Comment

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