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.