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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: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

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January 8, 2006

My Shopping List

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Posted by Derek

Some time ago I wrote about some atoms that I wish I could use. There are still other molecular fragments that Nature has neglected to provide, though, and I'm adding to the wish list:

First off, I'd like some groups that are plain linear spacers of different lengths. Ideally, we could stick these onto carbons and heteroatoms alike. As it stands, the only commonly available group that does this is an alkyne (a carbon-carbon triple bond), and those come with their own baggage. While there are drugs that have these groups in them, they're typically treated pretty roughly by the liver enzymes. A metabolically stable alkynish thing, of variable length, would be a wonderful thing. People have made various weirdo spacers out of small bicyclic systems, true, but the synthetic routes to them are beastly, with no improvement in sight. Until we can source these things by the kilo, drug companies aren't going to be interested.

Next, I'd like some six-membered heteroaromatic rings with something other than nitrogen in them. As it is, pyridines, pyrimidines, and pyrazines are given a real workout in drug discovery programs, and we'd love to have some more options. Unfortunately, the fabric of the universe hasn't accomodated us. If you put an oxygen in there instead, it has to take on a positive charge, and that gives you a highly reactive beast called a pyrylium. It's rare that you can get one of those into a bottle, and even if you did, sending one in for biological testing would be grounds for a referral to the HR department. I see that some zanies have tried, though.

Sulfur can do the same lively thing, although I've never actually seen any of those, and there's probably a good reason for that. Varioius sorts of aromatic rings with a phosphorus atom in them are known, but they're cranky and exotic, like a lot of phosphorus chemistry. Actually, a lot of phosphorus chemists are kind of that way, too, in my experience. Like a lot of phosphorus compounds, those aryls probably reek to the skies, too. As for phosphorus chemists reeking, I'd say my personal data set runs about fifty-fifty.

And finally, I'd also like some big, lumpy polar atoms. As it is, if you want to put a single lunker of an atom onto a molecule, you're looking at a bromine substitution. Iodine's possible and even larger, but those compounds are usually too unstable to sunlight to make good drugs, unless you're doing thyroid receptor ligands, where you might have to have them whether you feel like it or not. It's true that a trifluoromethyl group is kind of like a big halogen atom, too. But all these halogens make your molecule rather greasy, which is something we'd rather avoid. Something the size of a bromine that could hydrogen-bond and help its molecule go into aqueous solution would be a big hit. Quantum mechanics, being perverse, has not obliged.

Comments (5) + TrackBacks (0) | Category: Odd Elements in Drugs


COMMENTS

1. LNT on January 9, 2006 8:44 AM writes...

Derek, about your comment about new atoms for 6 membered aromatic groups...
I think that there is still a good deal of heteroaromatic groups yet to be utilized out there. (some of it due simply to synthetic accessability)
Unfortunately, I can't add a chemdraw file to this post, but imagine the following ring systems: (all pretty scarce in literature -- but certainly feasible to make)

1.) ortho or para pyridones substituted on nitrogen
2.) imagine replacing the carbonyl in the above pyridones with an SO2 or S=O.
3.) meta pyridone with a disubstitution on carbon (not aromatic, but would likely mimic an aryl ring)
4.) an aromatic ring containing an *internal* sulfonyl imine. (ie the 6 membered ring would have a N=S)

Certainly some of these would be hard to make and the metabolicly unstable, but you never know till you try. When you move into fused aromatic rings, there are still lots of possibilities out there yet to be explored. My personal favorate is trying to incorporate sulfur (especially oxidized versions of sulfur) into aromatic rings. It's often not hard to do and it really differentiates your molecules from all the others out there.
I also wonder if we'll all being trying to incorporate silicon and boron atoms into our molecules in another 5 or 10 years. I don't think either of those atoms have inherent toxicity issues.

Permalink to Comment

2. Derek Lowe on January 9, 2006 8:59 AM writes...

I wrote about silicon-containing drugs here a while back, from an era that I haven't gotten around to re-archiving yet. I agree that these kinds of atoms are gradually going to become more tolerated in medicinal chemistry, out of necessity.

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3. Harry on January 9, 2006 4:30 PM writes...

A bit OT, but Selenium heterocyles are fairly stable, and not too difficult to synthesize (aside from the fact that many Selenium compounds are horribly smelly). Some Selenium analogs of Sulfur compounds have been tested as antifungals and antibiotics (Klayman and Gunter devote a subchapter to these), but to my knowledge, none have panned out.

Apparently some of this work goes back to WWII, it's not clear from my reading if anyone has been pursuing this area in more recent times.

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4. Joseph Hertzlinger on January 9, 2006 4:55 PM writes...

What happens when a boron atom is part of a heteroaromatic ring?

Permalink to Comment

5. JK on January 9, 2006 5:39 PM writes...

A bit off topic, but I'm a curious non-chemist, and this seems as good a thread as any: are the first applications of "designer proteins" likely not going to be directly as pharmaceuticals, where the amateur biotech / nanotech enthusiasts often speculate, but in artificial enzymes that will make possible new organic syntheses?

From the outside this looks sensible to me. You get to focus on a single goal without having to worry about side effects or delivery.

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