Benign-by-Design: Can Drugs be Eco-Friendly?

There’s been scuttlebutt recently about what happens to drugs that have been, to put it bluntly, flushed out of our bodies and down drains and toilets. Scientists are becoming increasingly worried about the drug waste that makes it out into the environment and accumulates. But what if drugs were engineered to be more eco-friendly in the first place? Our own Sarah Everts took a look at the concept of building greener drugs in this week’s issue. As she says, “there is not yet an ecotoxicity equivalent to Lipinski’s Rule of Five,” the infamous set of parameters to predict the safety and orally-availability of a compound that were developed at Pfizer by Christopher Lipinski in the late 1990s. Still, scientists from academia and industry provided a few guidelines for a “benign-by-design” approach to medicinal chemistry: --Adding ester bonds can help with biodegradability. --Avoid quaternary carbons because they hinder biodegradability by microorganisms. --Eliminating halogens, a culprit in making a drug environmentally persistent. --Size matters, as bacteria cannot break down molecules that are too large. --Getting rid of potentially environmentally-unfriendly blocking groups that aren’t involved with a drug’s activity. --Increasing how efficiently drugs are absorbed when taken orally, so patients need to take less drug in the first place, lessening the amount that winds up in the environment --Exerting more control over when and how a drug degrades. Everts goes on to provide some examples of projects within pharma companies where a “benign-by-design” approach is yielding results. Still, there are hurdles, not the least of which is that an eco-friendly drug isn’t at the top of most companies’ priority list. So, what are you thoughts on the potential of “benign-by-design”? Is this at all a consideration in your company or university’s labs?

Author: Lisa Jarvis

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  1. This article portrays medicinal chemists in a somewhat unfair light. While it is true that environmental impact isn’t necessarily on the forefront of considerations made in designing drugs, some of the listed suggestions incorrectly put the onus on them.

    1) Add ester groups. Using esters as prodrugs to cover up acid functionalities dates back to aspirin. Suggesting this is a solution is just absurd. Google “first pass” to see why.

    2) Blocking groups. “Sometimes during synthesis, medicinal chemists add moieties such as blocking groups, which could end up in the final structure but are not required for activity.” This simply isn’t true. If a “blocking group” is placed on the molecule, that means it’s designed to block the activity of something that will degrade it. No medicinal chemist is just throwing blocks of inert material onto their compounds for no reason.

    3) Increasing oral bioavailability. It’s simply irresponsible to make it sound like medicinal chemists DON’T work towards this. As a matter of fact, this is a large part of the consideration in the Lipinski rule of 5. Achieving the proper balance of lipophilicity to make a druggable compound isn’t a matter of laziness, and to imply that scientists didn’t do everything they could at the time to make Lipitor as bioavailable as possible is a flat out lie.

    4) Exerting more control over when and how a drug degrades. If medicinal chemists truly had a handle on this wouldn’t they have implemented it already?

    The article ends with this sentence: “Although LASs are actually more toxic to aquatic organisms than TPS, they disappear quickly enough that they have become broadly accepted.” So it’s okay for something to actually be MORE harmful to the environment as long as it goes away fast enough for people to ignore it?

  2. Hey JBone, Sarah Everts here, the reporter for that story.

    Actually I would say that the onus, if anywhere, is on top management of pharmaceutical and biotech companies to prioritize a new drug’s long-term profile in the environment as a key factor in the triage process. Implementing the better environment profile would fall to the med chemists. As for how to do this: the dialogue has only just begun, and I won’t pretend to be an expert. The points I mention come from chemists who have been mulling over the problem, and like all science, I’m sure there’s bound to be some debate.

    I found your #4 point interesting, when you propose that if medicinal chemists truly had a handle on drug degradation in the environment, wouldn’t they already be doing it?! That’s pretty much the whole point of my article: Chemists don’t know how precisely how to improve a drug’s long term environmental profile, and as a community, they haven’t given it much thought–at least in the peer-reviewed literature. But now some chemists are starting to brainstorm. When green chemistry got going, early proponents have told me that they heard similar arguments from process chemists they were preaching to: If green process chemistry was possible, wouldn’t we be doing this already? Like process chemists, medicinal chemists have had their hands full with a lot of challenges, and perhaps the environment has not been a top priority. The fact that adopting green chemistry principles has eventually helped the pharma industry save billions of dollars, while also decreasing the environmental impact of drug production, gives me hope that maybe a drug’s environmental profile can itself be improved.

    Of course increasing oral availability is a major goal of medicinal chemists… I didn’t say otherwise. But if a drug such as Lipitor is only 12 % bioavailable, surely you’d agree there’s room for improvement!

    And as for your last point: When a life cycle assessment is made, people are sometimes forced to chose between non-ideal options. It makes sense to me that a nasty compound which quickly degrades in to something benign would be chosen over a persistent compound that behaves badly over a long period of time.

  3. Hi Sarah, thanks for the reply. As a point of note, I was not attacking your article or journalism, but rather the comments that were made by the people interviewed. In particular Dr. Cue’s comment about bioavailability I found inexcusable. As a Ph.D synthetic chemist, he of all people should know the challenges that face medicinal chemists in design/synthesis of new compounds. Saying “Hey, let’s increase bioavailability!” is tantamount to the CEO of Chrysler telling his engineers, “You know, our cars would run a lot better if you could make the engine more efficient.” That’s not news, it’s rhetoric, and people HAVE been working on that. To make that statement dismissively makes it sound as if scientists who worked on that project were lazy. It ignores some of the most challenging science that goes into drug development (ie; in vitro vs in vivo effects, discrepancies in dose/response between clinical trials, etc).

    Of course, what the whole issue boils down to is money. It’s likely that given enough time the drug discovery team could have developed a highly orally bioavailable analogue. The CEO’s don’t care about that, they care about when they’re going to have a drug that they can start selling to recoup the R&D burn rate and line their pockets with a little more green. So you’re right, the onus sits on them, but good luck convincing them that they need to sit on a compound they can sell so you can improve the bioavailability profile.


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