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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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January 24, 2013

Three Rings in a Row

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Posted by Derek

GRL.png
Here's a structure that caught me eye, in this paper from Georgia State and Purdue. That's a nice-looking group stuck on the side of their HIV protease inhibitor; I don't think I've ever seen three fused THF rings before, and if I have, it certainly wasn't in a drug candidate. From the X-ray structure, it seems to be making some beneficial interactions out in the P2 site.

This is an analog these are analogs of darunavir, which has two THFs fused in similar fashion. That compound's behavior in vivo is well worked out - most of the metabolism is cleavage of the carbamate. Both with and without that, there's a bunch of scattered hydroxylation and glucuronidation; the bis-THF survives just fine. (That's worth thinking about. Most of us would be suspicious of that group, but it's pretty robust in this case). I'd be interested in seeing if this new structure behaves similarly, or if it's now more sensitive to gastric fluid and the like. No data of that sort is presented in this paper (it's an academic group, after all), but perhaps we'll find out eventually.

Comments (5) + TrackBacks (0) | Category: Infectious Diseases


COMMENTS

1. felix on January 24, 2013 1:15 PM writes...

I wouldn't describe it as 3 fused THF rings, but rather as a diacetal.

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2. will on January 24, 2013 2:43 PM writes...

for what it's worth, Arun Ghosh (as in dARUNavir) is one of the authors, don't know if that means anything as far the clinical practicality of the compound

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3. milkshake on January 24, 2013 2:53 PM writes...

the same with topiramate - the two acetonides in the molecule are too metabolically stable, if anything. Over 70% of the orally administered drug is excreted unchanged through kidneys

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4. Esteban on January 24, 2013 4:54 PM writes...

"Three Rings for the Elven-kings under the sky" - J. R. R. Tolkien

I know, not a useful comment, and no, you may not have these 5 seconds back!

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5. Justin Peucon on January 24, 2013 5:14 PM writes...

Oligoannelated THF molecules are indeed a quite active topic. See e.g:
Org. Lett., 2009, 11 (11), pp 2317–2320
doi: 10.1021/ol900694m
9 fused rings!
Although, to my point of view, the most spectacular structures in this field have been obtained for bowl-shaped systems, for which beautiful X-ray structures have been determined:
(oxahomo)cubane : doi 10.1002/anie.198916631
Pentaoxa(5)peristylane: doi 10.1021/jo010222v

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