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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: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

« Buy! Sell! Shout! Moan! | Main | Amgen: The Pythian Oracle Laughs Again »

April 10, 2007

Sulfur, Your Pal. Mostly.

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Posted by Derek

I had a question the other day in my e-mail about various sulfur-containing functional groups in drugs. My answers, condensed, were as follows:

Sulfides: will always be under suspicion for oxidation in vivo. If that's your main mode of metabolism and clearance, though, then the problem can be manageable. Still, many people avoid them to not have to deal with the whole issue, and I can't blame them. I do the same. Since the reagents needed to prepare them tend to reek, it's a handy bias to have.

Sulfoxides: I spent quite a while on an old project turning out a whole line of these. I'm not sure if I'd do that again, though. Sulfoxides are interestingly polar, but they're also frustratingly chiral. If you need a specific right-hand or left-hand sulfoxide (and I did!), there are numerous not-always-appealing ways to get them. The other worry about them is that they can get either oxidized (up to the sulfone) or reduced back down to the sulfide. A good example of this problem is in the -prazole proton pump inhibitor drugs, which are probably the most prominent sulfoxides on the market. Some of them (like omeprazole) get oxidized, and others (like rabeprazole) get reduced. I've even heard of a chiral sulfoxide going in vivo and coming back out in the urine as the other enantiomer, via reduction and chiral oxidation. Many people prefer to avoid the whole issue - and after my experiences, I can't say I blame them here, either.

Sulfone: finally, a metabolically stable one. Sulfones have a reputation as rock-solid functional groups, at least when there aren't active hydrogens next to them. Of course, sometimes the compounds are also stable rocks that don't like to dissolve, but we have that problem with everything. I haven't come across anyone with an unkind word for sulfones.

Sulfonamides: If you're an experienced medicinal chemist, boy, have you cranked out some sulfonamides in your time. They're just so easy to make, and you can get so much structural variation out of them. But secondary ones (with a free NH) can get you into trouble in vivo, since they're so acidic. Acidic compounds can behave weirdly when they try to cross out of the gut or into cells, and have a reputation for hanging around in the blood forever. My bias has always been to go with sulfonamides that have fully substituted nitrogens, and I say let 'em rip.

So, those are my biases. Readers are invited to unload their buried feelings about sulfur functionality in the comments.

Comments (12) + TrackBacks (0) | Category: Life in the Drug Labs | Pharmacokinetics


COMMENTS

1. Bran at babybiotechs.com on April 10, 2007 11:52 AM writes...

IMHO, sulfur stinks. :)

Permalink to Comment

2. Wavefunction on April 10, 2007 12:06 PM writes...

Sulfonamide containing drugs many times are also diuretics- often an undesirable property. For example, chlorothiazide has a sulfonamide side chain and has strong diuretic properties, which led to clipping off the group to give the antihypertensive Hyperstat. Of course, chlorothiazide itself began to be used as a clinical diuretic! Two birds with one stone.

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3. Hap on April 10, 2007 12:21 PM writes...

As a bonus, primary arylsulfonamides are a standard carbonic anhydrase-binding motif (aryl, naphthyl, and heterocyclic), which almost guarantees them to be diuretics. I don't know if they crystallize well either.

Permalink to Comment

4. the evil resident on April 10, 2007 12:24 PM writes...

@Wavefunction: What was chlorthiazide's original indication?

@Derek: Just how cross-reactive are these functional groups? I sometimes worry about the theoretical cross-reactivity between sulfonamide antibiotics, sulfonylureas, and thiazides, particularly since allergies to sulfonamides seem to be relatively common, and adverse effects like Stevens-Johnson really freak me out. And then there's the theoretical idea of causing hypoglycemia. Does any of this ever actually happen?

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5. milkshake on April 10, 2007 1:13 PM writes...

many sulfur-containing heterocycles are quite well behaved - thiazoles, izothiazoles, thiadiazoles, benzthiazoles, etc.

sulfones and sulfonamides are huge polar groups so if you put them in the molecule you have to limit number of amide NH

Permalink to Comment

6. Derek Lowe on April 10, 2007 1:29 PM writes...

Oh, there's no way I'd put in a primary (hetero)aryl sulfonamide. Carbonic anhydrase, matrix metalloproteases, all sorts of other stuff that has a zinc in the active site - it's just asking for trouble. Tertiary ones are, to the best of my knowledge, safe from all this stuff.

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7. The Dude on April 10, 2007 4:16 PM writes...

Speaking of sulfur, nobody has mentioned thiophenes. These molecules are common as "table builders" in a lot of methodology papers, but are there any drugs out there containing the thiophene group?

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8. Drew on April 10, 2007 6:35 PM writes...

Thiophenes are often phenyl surrogates, due to the larger radius of S....

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9. Bri76 on April 10, 2007 7:12 PM writes...

I do not think it would be accurate to label Cramer a short termer. It is true he does not subscribe to buy and hold (who should? Ford, Sun Micro, IBM, etc, etc, etc.). If I could capsulize his picks, it would be to buy and hold until you lose 8% of purchase price. Start scalping your gains once you reach 20%. A small example in an arsenal of advice he dishes out. His advice on picking stocks is very sound. People should not focus so much on his individual stock picks.

People look at his picks one week after he announces them and start unfairly judging him. It would be better to look at his picks over a 6 month period. BTW, great blog.

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10. Bunsen Honeydew on April 11, 2007 9:00 AM writes...

Thanks for the post Derek; I appreciate it.

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11. chemistry is hilarious on April 11, 2007 12:08 PM writes...

In light of this post, I would be interested to hear your take on some other sulfur groups... sulfonates, sulfinates, thioesters, etc. I know fluticasone has a thioester, but I can't thnk of anything that would have the other two. Too acidic? I'd imagine they would do wonders for solubility in a greasy compound.

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12. rosko on April 12, 2007 2:27 PM writes...

"Speaking of sulfur, nobody has mentioned thiophenes. These molecules are common as "table builders" in a lot of methodology papers, but are there any drugs out there containing the thiophene group?"

I don't know of any offhand that contain a thiophene ring by themselves (there probably are some), but I know a few that have one as part of a fused ring system. In particular, the atypical antipsychotic olanzapine contains a tricyclic system with a thiophene, and the estrogen receptor modulator raloxifene has a benzothiophene core.

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