Taking a hint from one of the comments to the last post, I took at look at a recent article in Chemical Reviews, where some folks at Boehringer Ingleheim did the heavy lifting of figuring out how many chiral and achiral drugs have made it to the marketplace in recent years.
I've taken the liberty of turning two of their categories into a graph, shown below. You can see that the percentage of new drugs that are achiral has indeed been decreasing, while the percentage of single enantiomers has increased. I'd like to have some more recent data to see if 2003 was an anomaly or not, but the trend is surely real. (In case you're wondering, the rest of the launches for any given year fell into the categories of natural product/semisynthetics, which I didn't count, racemates (which have basically dwindled to nothing across this time span) and proteins, antibodies, polysaccharides and such).
And I'd like to clarify my point from yesterday: it's not that I don't work on projects that turn out chiral development candidates. In fact, in recent years I've probably worked on more projects that recommended a chiral final compound than an achiral one. But in the drug discovery phase, I do avoid chiral centers until I can see if they're worth exploring. If they're not, then so much the better, as far as I'm concerned.
Take a piperidine, for example, a structural subunit that's every medicinal chemist's friend. As a commentor noted yesterday, if you stick a piperidine on your molecule, attached through the nitrogen (and who hasn't?), you have several choices if it comes back active. You'll probably start varying the substituents on the piperidine ring, since you can buy a lot of them. The first ones will probably be the 4-substituted series, since they're not chiral.
Now, I'll make and send in 3- and 2-substituted ones as well, but I'll probably use things like racemic 3-methylpiperidine first, just to see if it's any good at all. Note that I'm talking about the first binding assay here - if you're going into cells, tissues, animals, tox assays and all that, you want a single enantiomer. But you're only going to do all those things if the compound binds well in the first place. If it comes back as a fifty-micromolar stinkpot, who cares? Odds are that synthesizing the single enantiomers will not suddenly reveal a nanomolar wonder drug. On the other hand, if the racemic 3-methyl comes back good (or even better than the 4-substituted analog), then it's worth checking the enantiomers, because that means that this part of the molecule is probably seeing the chiral protein up close. (Readers with subscriptions to Bioorganic and Medicinal Chemistry Letters can see for themselves that I have not pulled that example out of thin air).
Unless I've got a lot of manpower or a big keg of starting material with an easy purification at the end, I'm probably not going to start off by making all the enantiomers of those chiral groups just to check them in the first assay. Ars longa, vita brevis, y'know. If they all come back bad, it's clear that you've wasted all your time. And if the chirality matters, the activity is going to be all in one series (most likely), in which case you've only wasted half your time. I don't see the upside.
1. milkshake on October 13, 2006 12:49 AM writes...
Having 4,4-disubstituted piperidine with two identical substituents makes it even more non-chiral :)
Permalink to Comment2. vent on October 13, 2006 3:41 AM writes...
Inactivity of a racemic mixture always raises the same question here. "Is it possible that one enantiomer antagonizes the activity of the other?"
We have seen an example of this once. The question comes back ever since.
My reply :"When someone asks this question it is because they know the answer. It is possible, but unlikely, and not worth doing chiral separation."
Permalink to Comment3. Jeremiah on October 13, 2006 12:27 PM writes...
The sudden bump in chirality is probably attributed to releasing additional patents for a specific enantiomer of a drug to avoid the patent loss.
Permalink to Comment4. weirdo on October 13, 2006 2:04 PM writes...
"The sudden bump in chirality is probably attributed to releasing additional patents for a specific enantiomer of a drug to avoid the patent loss."
I don't think so. That canard comes up time and again and just does not stand up to scrutiny.
Skimming through "Annual Reports" 39 and 40, I see one "enantiomer switch" (atomoxetine) in 2003, and 2004 did not seem to have any.
Someone feel free to disagree, but back it up with some data . . .
Permalink to Comment5. gc on October 13, 2006 4:03 PM writes...
Derek,
Shocked!
You finally gave us evidence of where you work.
gc
Permalink to Comment6. Derek Lowe on October 13, 2006 4:11 PM writes...
gc, colleagues of mine at the Med-Chem Gordon conference reported back to me that it wasn't much of a secret inside the industry, and my name has appeared in print next to the company's before. I'm still not going out of my way to identify my workplace, and won't comment on its doings other than in the most general way, but I figure that anyone who reads (or follows a link to) BOMCL knows where I am, anyway.
Permalink to Comment7. random process guy on October 13, 2006 4:30 PM writes...
Derek,
I don't think the proponents of deliberately designing chiral molecules understood your original point because they don't have an idea of what stage of drug development you're talking about. Hopefully, they do now.
I'll clarify a bit more. The commercial drugs that are chiral got that way through a LOT of trial and error, and I'll go out on a limb here and say that almost any analog you can think of that is achiral at any given stereocenter has been tried and has failed. Chirality is costly, therefore it had better bring value to the drug candidate.
A figure showing the number of achiral versus chiral drugs really doesn't have anything to do with the reason you try to avoid chiral centers in your analoging (is that a real verb?). Chirality is brought into a drug by necessity, not preference.
Permalink to Comment8. pharmachick on October 24, 2006 12:01 AM writes...
About chirality and activity ... recently in a sub-the field that I make a valiant effort to contribute to, a suspicious number of compounds have turned out to be specific substrates for enzyme isoforms but ONLY one of the enantiomers is specific (oxazepam and lorazepam to name a couple off the top of my head - and these are each specific for *different* isoforms despite both being from the same class).
So my thought is - are the DM guys driving this chirality issue? The superfamily for which this applies are major clearance enzymes and second most important after P450s for drug metabolism (i.e. the UGTs).
Permalink to Comment9. Chris on October 31, 2006 3:37 AM writes...
I doubt that you proceed in such a stepwise manner, more likely you would make a "library" of 2, 3 and 4 -substituted piperidines and remake/resolve the actives :-).
What would be interesting would be find out if chiral drugs have advantages over achiral drugs? Are they less likely to be metabolised, be CYP inhibitors, PGP substrates or some other off-target activity? Perhaps just compare the development timelines?
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