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January 24, 2013
Three Rings in a Row
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.
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