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.