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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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« Five Things I Haven't Used in Years | Main | More Handedness »

October 11, 2006

On The Other Hand

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Posted by Derek

My mention of hardly ever taking an optical rotation led into the question of what to do about chirality in drug candidates. One commentor mentioning hearing someone from one company making a big deal out of including chiral fragments in their molecules, which seemed to contradict my attitude.

It sure does - but I'm right. Well, on this issue I am, anyway. Chirality can be a great help, but it's often purchased at a great price. It's true that our molecules are interacting with chiral protein binding sites, which should mean that the right optically active compound is probably the best fit you can get. But how long will it take you to get there, and what are you willing to pay?

There are chiral centers and there are chiral centers, of course. The ideal situation is a single chiral carbon that you buy from a cheap source (a naturally occurring amino acid, say) which quickly gets turned into something non-epimerizable. That's not so painful, and if it buys you better activity, then why not? Compare that to the other end of the deal, which might be something that can't be purchased cheaply and requires a from-the-ground-up chiral synthesis. It's either that or a good old fashioned resolution, which means that half your work and money has to be thrown away. Throw in some chances of racemization and you're looking at a real campaign, which you'd better have a good reason to embark on.

Other things being equal, I try to avoid chirality. There are plenty of achiral compounds out there that have earned billions of dollars, after all, so why go looking for trouble? If I add a chiral center, I try to make it something that's available cheaply, not some exotic creature-from-the-chiral-lagoon stuff that goes for a dollar a milligram on the easier enantiomer. There's almost always something else you could be doing rather than going down that path.

Still, I'm pretty sure that the number of chiral drugs (outside of natural products) has been increasing over time, although I'd like to know just how much. I'm not sure that I believe the chart here, for example, and I'd like to split out the cases where someone comes in selling a single enantiomer of a formerly racemic compound. But newer reactions are putting more and more chiral chemical space into the "worth a try" category. So I don't fear handedness in my compounds - but I don't seek it out, either. If that interviewer from Company X really does, well, my achiral compounds and I will just watch from a safe distance.

Comments (21) + TrackBacks (0) | Category:


1. Handles on October 11, 2006 10:28 PM writes...

I find it really elegant when a med. chemist puts in a symmetrical carbon instead of a chiral centre. Two examples I can think of are oseltamivir, where the pentyl ether sidechain is sooo much cooler than the corresponding hydroxylated monster in zanamivir, and secondly fluconazole (cf. voriconazole).

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2. Jeff Bonwick on October 12, 2006 12:40 AM writes...

It seems that most single-enantiomer drugs have been introduced to extend patent lifetime, not to improve efficacy or reduce side effects (of the inactive half).

For drug discovery, it would seem that the only case you have to worry about is 'false toxicity' -- that is, one enantiomer kills cancer but the other kills everything. Any idea how often that happens in practice?

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3. Robin Goodfellow on October 12, 2006 2:51 AM writes...

The classic example in this vein is probably thalidomide. R-thalidomide is an effective sedative (and possibly a powerful anti-inflamatory), S-thalidomide causes very severe birth defects. However, thalidomide becomes racemic in the human body so you get no advantage from selective synthesis.

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4. Process Chemist on October 12, 2006 8:09 AM writes...

I just did the math: 18% of the projects I worked on during my career in pharma were achiral molecules. The one I'm working on right now has 3 chiral centers. I am in Process, so these have all gone through the Med. Chem. sieve. Am I working on a different industry?

Keep making planar molecules Derek, you're making it easier for us (your competitors).

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5. MolecModeler on October 12, 2006 9:36 AM writes...

From a comp chemists perspective, I always try and design achiral molecules. Hard enough to get a chemist to make something, if you include a chiral center...forget it. However, one chiral center can make a huge difference in all kind of properties, nothing you could predict of course.

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6. Ashutosh on October 12, 2006 11:01 AM writes...

One advantage of chiral drugs is that you can always get a new patent on the single enantiomer later, when formerly you were seeling the drug as a racemate (eg. Omeprazole). Echoing MolecModeler above, these days, computational structure based drug design studies do try to come up with compounds that have minimum or no chiral centers. In our project, we did do that, and luckily, that compound turned out to be the most potent of all analogs.

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7. milkshake on October 12, 2006 11:42 AM writes...

The number of chiral pieces used in pharma will grow as chiral HPLCs and asym reactions are getting more user-friendly. Recently I had a very good experience with Noyori transfer hydrogenation of acetophenones, with aqueous sodium formate as reducing agent.

The process chemists experience can be different - it is common that the early medchem series are achiral or racemic, only in later stages the homochiral compounds are made, because of selectivity etc. Also FDA does not want companies to develop racemic drugs anymore so one has to come up with a good process route to a single enantiomer.

But as Derek pointed out - If I need to try some monosubstituted piperidines in my project, the very first ones that will get made and tested will be the 4-substituted ones.

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8. weirdo on October 12, 2006 12:09 PM writes...

"One advantage of chiral drugs is that you can always get a new patent on the single enantiomer later, when formerly you were seeling the drug as a racemate (eg. Omeprazole). "

No, you can't. You're assuming the FDA will let you test (let alone register) a racemate. And you're assuming the PTO will allow a patent on a pure enantiomer in the future.

No right-minded company will take forward a racemate without making and testing the enantiomers. If you have that data and withhold the information from the PTO, you risk losing the patent on everything. So what you suggest is not really a viable strategy any more.

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9. Ashutosh on October 12, 2006 12:30 PM writes...

I was not aware that the FDA does not allow racemates anymore. But in the past, it does seem to have happened for drugs; that was the whole concept of 'racemic switches'. I do know it happened with Prilosec (AstraZeneca); the FDA initially approved the racemate and then approved the single enantiomer. But as you and milkshake point out, the rules seem to have changed since then.

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10. MTK on October 12, 2006 12:51 PM writes...

The FDA does not have a specific rule against racemates, but if you want to push a racemate through you have to prove that both enantiomers are bioequivalent in every respect, which is damn tough to do. Even if the chiral center racemizes in vivo, you probably have to show that the rate of racemization is the same for each enantiomer or least faster than other processes such adsorption or metabolism. In practical terms, you're better off developing the single enantiomer. That was not true in the past. I know of no company which would consider developing a racemate anymore.

Having said that, at least early on in a discovery program, I'm not sure why someone would bother with a chiral synthesis. First choice would be an achiral molecule, but if a chiral center is there and the one enantiomer is active and the other inactive, so what? One half of nanomolar activity is still nanomolar activity. Save some time, make it racemic, find your lead, then worry about the enantiomers.

Later on however I can specifically recall a number of times, when I pointed to a chiral center with a methyl group and said, "What happens when that's a gem-dimethyl?"

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11. Chemist of Sorts on October 12, 2006 12:57 PM writes...

Hasn't Sepracor made a business model out of patenting single entantiomers of blockbuster drugs and then selling them back to the original companies?

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12. Don B. on October 12, 2006 1:13 PM writes...

Please look at the differing human efficacy of Lovastatin(TM) racemic compared to Zocor(TM), Crestor(TM) and Lipitor(TM).

Think of all of the patients that have been helped by developing, producing, and selling the "correct" enantiomer.

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13. Derek Lowe on October 12, 2006 1:44 PM writes...

I was under the impression that lovastatin had always been optically active, since it was largely derived from fermentation. I believe that the differences between the various statins are due to other factors.

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14. MTK on October 12, 2006 1:59 PM writes...

Don B.,

Those are four different compounds, not a racemic version vs. a single enantiomer.

No one is doubting that single enantiomers are a better idea than racemic drugs. The point is that there is a time and place for everything, and that early in the drug discovery process, meaning hit generation or hit to lead, the extra work required to get the single enantiomer is often just not worth the effort. After that, it's critical. Before that, it's questionable.

And if you can find something achiral that's just as good, even better.

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15. MTK on October 12, 2006 2:03 PM writes...

Ooops, you beat me to it, Derek.

Lovastatin and simvastatin are from fermentation and are not racemic. The difference between the two is that simvastatin has one less chiral center due to an alpha-methyl ester in lovastatin being a gem-dimethyl ester in simvistatin.

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16. process wannabe on October 12, 2006 2:22 PM writes...

There was a recent paper (Chem Rev. 2006, 106, 2734: DOI) on asymmetric synthesis of API's that has some good data on the number of achiral versus chiral drugs coming to market, as well as the method of achieving the correct enantiomer. Good reading.

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17. weirdo on October 12, 2006 3:24 PM writes...

"early in the drug discovery process, meaning hit generation or hit to lead, the extra work required to get the single enantiomer is often just not worth the effort."

Really? I don't want to work in that company!

We routinely look at cross-reactivity, p450 inhibition, hERG inhibition, etc. early in the discovery process. Throwing a molecule out based on how a racemate performs in such screens is silly.

Also, I saw the comment that a "nanomolar racemate is still a nanomolar pure enantiomer". I guess it depends upon the assay. Sure, if you only looking at binding. If you are using any kind of functional assay, all bets are off.

Screening racemates is great, but if you don't get pure enantiomers before you start doing any kind of real decision-making, you're just doing bad medicinal chemistry.

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18. MTK on October 12, 2006 4:49 PM writes...


I didn't say that you would throw out a molecule based on how it's racemate performed. In fact, in some ways I'm arguing the opposite. And I was talking about binding.

I guess it depends on what the definition of lead op vs. lead generation is, but if you're already looking at P450, hERG and such then you're further in the process than I was alluding to. (Of course, I realize that those things are done earlier and earlier these days.) That's why I said, at some point it's critical to get the enantiomer, which is exactly what you're saying. I think we're actually in agreement.

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19. weirdo on October 13, 2006 9:53 AM writes...

Yeah, I see where you are coming from now, thanks.
But didn't you forget the part where you rip off NIH-funded academic investigators for all you best ideas? ;o)

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20. MTK on October 13, 2006 11:38 AM writes...


Don't sell me short! I don't limit myself to ripping off just NIH funded folks.

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21. Dustin James on October 13, 2006 1:11 PM writes...

Chemist of Sorts: "Hasn't Sepracor made a business model out of patenting single entantiomers of blockbuster drugs and then selling them back to the original companies?"

Sepracor did not necessarily sell their IP on single enantiomers back to the company that made the racemate. They did whatever made them the most money, as I see it. They have started their own drug development--Lunesta for instance. I first became aware of Sepracor when they were using a combination of enzymes and membrane separation to preferentially hydrolyze one enantionmeric ester over the other, in the NSAID arena, i.e. producing S-ibuprofen. There are lots of smart people in that company.

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