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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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July 18, 2012

The Best Rings to Put in Your Molecules?

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Posted by Derek

Here's a paper from some folks at GlaxoSmithKline on what kinds of rings seem to have the best chances as parts of a drug structure. They're looking at replacements for plain old aryl rings, of which there are often too many. Pulling data out of the GSK corporate collection, they find that the most common heteroaromatic rings are pyridine, pyrazole, and pyrimidine - together, those are about half the data set. (The least common, in case you're wondering, are 1,3,5-triazine, 1,3,4-oxadiazole, and tetrazole). In marketed drugs, though, pyridine is more of a clear winner, and both pyrrole and imidazole make the top of the charts as well.

When they checked the aqueous solubility of all these compounds, the 1,2,4-triazoles came out on top, and the 1,3,5-triazines were at the bottom, which sounds about right. Other soluble heterocycles included 1,3,4-oxadizole and pyridazine, and other bricks were thiazole and thiophene (not that that last one really counts as a heterocycle in my book). Update: I've revised my thoughts on that! Now, you might look at these and say "Sure, and you could have saved yourself the trouble by just looking at the logD values - don't they line up?" They do, for the most part, but it turns out that the triazines are unusually bad for their logDs, while the five-membered rings with adjacent nitrogens (all of 'em) were unusually good.

The next thing the team looked at was binding to human serum albumin. The 1,3,4-thiadiazoles emerged as the losers here, with by far the most protein binding, followed by thiazoles and 1,2,4-oxadiazoles. Imidazoles had the least, by a good margin, followed by pyrazine and pyridazine. Those last two were better than expected compared to their logD values.

And the last big category was CYP450 inhibition. Here, thiophene, tetrazole, and 1,2,3-triazole were the bad guys, and pyridazine, 1,3,4-thiadizole, and pyrazine (and a few others) were relatively clean. The people at AstraZeneca have published a similar analysis, and the two data sets agree pretty well, with the exception of oxazole and tetrazole. The AZ oxazoles all had open positions next to the ring nitrogen, which seems to have opened them up to metabolism, but the difference in tetrazoles (AZ good, GSK bad) is harder to explain.

The take-home? Pyridazine, pyrazine, imidazole and pyrazole look like the winners from an overall "developability" score. Thiophene brings up the rear, but since I still think that one shouldn't count update (it's a benzene in disguise), the ones to worry about are then thiazole, 1,2,3-triazole, and tetrazole (that last one with an asterisk, due to the CYP data discrepancy).

The paper tries to do the same analysis with heteroaliphatic rings, but the authors admit that they had a much smaller data set to work with, so the conclusions aren't as strong. There was also a higher correlation with plain ol' logD values across all three categories (not as many surprises). The winners turned out to be piperidine NH and morpholine N-alkyl, with imidazoline and piperidine N-alkyl right behind. The losers? Piperidine N-sulfonamide, followed by pyrrolidine N-sulfonamide, and then 1,3-thiazolidine. (Sulfonamides continue to live up - or down - to their reputation as Bad News).

There are, naturally, limitations to this sort of thing. Ceteris paribus is a mighty difficult state of affairs to achieve in medicinal chemistry, and other factors can rearrange things quickly. But if you're just starting out in an SAR series, it sounds like you might wand to give the pyrazines and pyridazines a look.

Comments (14) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. Anonymous on July 18, 2012 11:29 AM writes...

Derek, the two links point to the same place, not different papers.

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2. Will on July 18, 2012 11:53 AM writes...

Given the success of the sartan class of angiotensin antagonists, I would not be too quick to dismiss the tetrazole

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3. Derek Lowe on July 18, 2012 12:11 PM writes...

Fixed the second link - thanks!

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4. Henning Makholm on July 18, 2012 12:26 PM writes...

Um, not a chemist here, but what did the poor thiophene do to you not to be considered a heterocycle? Does it spontaneously rearrange to put the sulphur outside the ring or what?

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5. milkshake on July 18, 2012 2:31 PM writes...

I love benzfurazanes - easy preparation from nitroanilines, good patent position, good metabolic stability, more polar but more el deficient than phenyl, act as a decent isosteric replacement of a nitrophenyl group. Mildly explosive but there are several process papers in OPR&D on benzfurazane drug candidates.

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6. sean on July 18, 2012 4:10 PM writes...

Will this be more useful than Lipinski's rule-of-thumb (I mean 5)?

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7. David Formerly Known as a Chemist on July 18, 2012 4:19 PM writes...

Sorry Derek, but I've personally seen multiple examples in several series where switching from thiophene to phenyl led to several log orders of activity loss, or led to greatly increased plasma protein binding, or some other drastic physicochemical change. I can't agree that a thiophene is a benzene in disguise (if so, it's a very poor disguise).

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8. milkshake on July 18, 2012 7:43 PM writes...

The two important differences between thiophene and benzene are 1) easy thiophene oxidative metabolic ring opening - this could be curse or unexpected blessing, see for example clopidrogel 2) Thiophene sulfur (and also thiazole sulfur) bears a significant partial positive charge and therefore likes to coordinate to lone el pairs of carbonyl oxygens and pyridine/pyrimidine nitrogens. This can contribute to stronger binding in active site but more importantly in drugs like kinase inhibitors (that contain several heterocycles) the S...O=C or S...N interaction locks in one particular planar conformation on the part molecule.

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9. Anonymous on July 18, 2012 8:02 PM writes...

Call me crazy, but I thought the point of tetrazoles and sulfonamides was more to mimic acidic moieties?

Any words on lactams (lactones) or cyclic (thio)ureas?

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10. MoMo on July 19, 2012 9:41 AM writes...

Pyrazines and their lone pair N atoms give them special properties-they act like water-soluble benzenes.

Good paper for paper chemists!

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11. Ever Decreasing Circles on July 19, 2012 12:28 PM writes...

Have I got this right?

Take a list of marketed drugs, find a descriptor (any descriptor) that distinguishes them from your in-house/patented compound collection and publish a paper announcing "Four legs good, two legs bad".

What does this this say about the confidence and vigour of small molecule Drug Discovery?

One thing is certain: any more of these rules and the only structures left as "acceptable" to develop will be those already on the market.

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12. ThirdWheel on July 19, 2012 12:39 PM writes...

Repeat after me, correlation is not causation, correlation is not causation, correlation is not causation....

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13. TX raven on July 20, 2012 12:47 AM writes...

@ 11 and 12:

You hit the nail in the head.

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14. Joe Lyon on July 20, 2012 8:26 AM writes...

Derek, have you got the right AstraZeneca paper? -there's one in Medchemcomm published last week that seems more relevant:
http://dx.doi.org/10.1039/C2MD20155K

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