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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: Twitter: Dereklowe

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December 1, 2008

Prodrugs: How the Pros Do It?

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Posted by Derek

I’m going to write this morning about a question that actually came up among several of us at the train station this morning. I’m on a route that takes a lot of people into Cambridge, so we have a good proportion of pharma/biotech people on board. And today we got to talking about prodrugs: like 'em or hate 'em?

For those not in the business, a prodrug is a masked form of an active drug, designed to be activated once it’s dosed. That’s generally done by allowing the normal metabolic processes of the body to clip some group off, revealing the real drug. Various esters are the most common prodrugs, since that’s about the easiest group to have fall apart on you. (Enalapril / enalaprilat is a classic example, and aspirin is an even more classic one).

And esters illustrate another point about prodrugs: no one develops them unless they have to, as far as I’m concerned. After all, if your compound works fine in its native form, why get fancy? No, I think you turn to the prodrug strategy when there’s something wrong. Maybe the active form of the drug isn’t well absorbed from the gut, or has too short a half-life in the blood, or doesn’t distribute to the right organs. The differences in these properties between carboxylic acids and their esters can be particularly dramatic.

There are other ways to do it. Some compounds are oxidized by liver enzymes to turn into their active forms, for example. But all of these ideas suffer from several complications, which is why I’ve always regarded them as acts of desperation. For one thing, all these metabolic pathways vary a good deal between species. That’s a problem for any drug development effort, of course, but you’ve doubled those headaches (at least) by working with a prodrug. Now you have to wonder, when you finally get to humans, if the conversion of the initial compound will take place to the same extent, as well as about the clearance of the active drug (and, for that matter, the non-productive clearance of the prodrug molecule itself). For a development group, taking on a prodrug can be like taking on two drugs at the same time.

There have been all sorts of ingenious ideas along these lines over the years. It’s been my impression that delivery methods of this sort have been more popular among academic medicinal chemistry groups than they have in industry, to be honest. There are all sorts of schemes for targeting active substances to particular organs, or for getting them into hard-to-reach areas like the brain through use of exotic prodrug groups. Most of these don’t survive exposure to the real world, but I can’t turn up my nose at them, either, because these are all things that we would like to be able to do in this business. If weird ideas don’t get tried, we’ll never find out if any of them actually work.

And there have been some real successes in the prodrug field, and it’s always an idea that comes up whenever a lead compound series shows some undesirable absorption or excretion. I’ve broached the topic a few times myself on past projects. But every time, we’ve been able to solve the problem by less drastic means – a new formulation, a salt form, or by just plain old going to a different compound in the end. If you can do it by some combination of those, I'd say you're probably better off in the end. (For those who are taking the plunge, you can probably learn about as much as can be learned from the literature here). Here's an even more recent review.

Comments (12) + TrackBacks (0) | Category: Drug Development | Pharmacokinetics


1. milkshake on December 1, 2008 9:50 AM writes...

Have seen the structure of GS9212, a new phosphonate-nucleotide analog for treatment of lymphoma from Gilead/A. Holy group, now in clinic? That monster is doubly pro-druged, times two: two L-alanine ethylester phosphoramidate groups have to be burned off from the phosphonate, together with the cyclopropyl from the purine amino, which itself has to be further de-aminated to to turn it into active antimetabolite that gets doubly phosphorylated and then finally crews up nucleosynthesis (by being incorporated into DNA and terminating the chain). That is a tour de force design.

The interesting point is that the pro-drugging itself is the key to the drug selectivity. The active metabolite has awful kidney toxicity so it cannot be used as such but it does not get released into circulation once it forms inside the cell, and the pro-drug activation happens selectively only in lymphatic tissue.

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2. petros on December 1, 2008 10:24 AM writes...

The BI thrombin inhibitor dabigatran etexilate is also a double prodrug.

Another useful tool is the antedrug, popular in inhaled respiratory products. Most inhaled steroids are esters that are readily deactivated when swallowed so that systemic (side) effects by minimized both due to the route of administration and rapid deactivation.

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3. LabRatUK on December 1, 2008 12:09 PM writes...

A some of this beastly molecules become larger, simply moving to a new salt/formulation does not always provide a 'way out' like it tradionally has. With some of these molecules it's simply impossible to 'dial up' a salt with adequate properties for development (believe me I know). I believe prodrugs may offer a way around this in some cases. If you can get to your Medchem teams early enough of course....!

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4. Hap on December 1, 2008 1:04 PM writes...

Does prodrug formation cancel out some or all of the effects of high molecular mass? If the drug starts out big, and you generate a prodrug for it, the prodrug is going to be bigger - unless the prodrug circumvents the liabilities of high MW, it's never going to into the body and its advantages in specifity won't help. For high MW compounds, formulation and salt formation would appear to be more general than prodrug formation.

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5. milkshake on December 1, 2008 3:11 PM writes...

High MW is not a terrible offense against drugability as such - if you manage the H-bond donor number and greasiness within a reasonable range.

Bigger molecules have increased tendency to be metabolized (cytochromes love large flat greasy molecules) - not necessarily a bad thing in a pro-drug.

I was involved in prodruging a molecule that was terribly insoluble (SU5416) and the original IV formulation with Cremofor made the patients very unhappy. A colleague found a nice shelf-stable soluble prodrug that had glycerol-derived carbamate appendage stabilized by a phosphate group that took advantage of a safety-catch effect. (Dephosphorylation in plasma made the appendage to cleave itself off promptly). Meanwhile the management decided that they would advance a more potent and soluble analog (SU11248) so all this work went to nothing.

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6. processchemist on December 1, 2008 4:29 PM writes...


Are you another victim of a PFE takeover? :)

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7. milkshake on December 1, 2008 5:07 PM writes...

The prodrug saga actually ended long before the merger and the layoffs. (I wrote some reflection on that date which will live in infamy, in "Such, such were the joys"). I don't blame management for killing this particular project. A murder was what later happened to all other pre-clinical compounds we had.

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8. HelicalZz on December 1, 2008 5:29 PM writes...

The February 2008 issue of Nature Reviews: Drug Discovery had a nice review of prodrugs.


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9. daen on December 1, 2008 10:48 PM writes...

I'm reminded of the oral thrombin inhibitor, melagatran, its double prodrug being ximelagatran. In one article ("A new oral anticoagulant: the 50-year challenge", Nature Reviews Drug Discovery 3, 649-659 (August 2004)) the researchers discuss the "challenges" in its development. I bet! Unfortunately it seems that some of these "challenges" carried forward, and AZ withdrew ximelagatran from the market in early 2006 on concerns about liver damage. So it goes.

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10. researchfella on December 1, 2008 10:49 PM writes...

Derek, I don't think aspirin is a pro-drug. Rather, it acetylates a serine residue in COX to act as an "irreversible" COX inhibitor. In fact, I'e always considered it to be a 'classic' example of an irreversible inhibitor that was a successful drug.
Wikipedia describes the mechanism of action for aspirin along these lines, so of course it must be true.

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11. I'm pro drug(s) on December 2, 2008 9:28 AM writes...

When does a pro-drug stop being a pro-drug and become a separate NCE? For example, BMS and Endocyte are moving forward in the clinic with a folate-epothilone conjugate, wherein the folate moiety purportedly results in targeting and selective uptake in tumor cells. The resulting death of those cells, however, results from the release of the epothilone. Would one still consider this a pro-drug? I suppose it is, but clearly (if it's true) much more is being added than simply overcoming a metabolism issue. What about the companies developing nanoparticles? E.g. polymer based systems carrying both active payloads, as well as targeting moieties, and also have passive targeting via the EPR effect? I think there is a lot of potential for innovation here - there's more to pro-drugs than adding an ester to cross the gut wall.

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12. Zaphod on December 3, 2008 7:23 PM writes...

So what are your general thoughts on macromolecule/polymer prodrugs? Lots of folks are conjugating PEG onto small molecule drugs and biologicals to try to take advantage of the EPR effect, and perhaps extended serum half-life for biologicals. Is there an opportunity to test out polymers other than PEG or is this just in the realm of academic interest? I guess I'd be worried about unwanted immune responses from other polymers but then PEG is so limited...

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