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July 19, 2012
Come Back Thiophene; All Is Forgiven
A couple of commenters took exception to my words yesterday about thiophene not being a "real" heterocycle. And I have to say, on reflection, that they're right. When I think about it, I have seen an example myself, in a project some years ago, where thiophene-for-phenyl was not a silent switch. If I recall correctly, the thiophene was surprisingly more potent, and that seems to be the direction that other people have seen as well. Anyone know of an example where a thiophene kills the activity compared to a phenyl?
That said, the great majority of the times I've seen matched pairs of compounds with this change, there's been no real difference in activity. I haven't seen as many PK comparisons, but the ones I can think of have been pretty close. That's not always the case, though: Plavix (clopidogrel) is the canonical example of a thiophene that gets metabolically unzipped (scroll down on that page to "Pharmacokinetics and metabolism" to see the scheme). You're not going to see a phenyl ring do that, of course - it'll get oxidized to the phenol, likely as not, but that'll get glucuronidated or something and sluiced out the kidneys, taking everything else with it. But note also that depending on things like CYP2C19 to produce your active drug for you is not without risks: people vary in their enzyme profiles, and you might find that your blood levels in a real patient population are rather jumpier than you'd hoped for.
So I'll take back my comments: thiophene really is (or at least can be) a heterocycle all its own, and not just a phenyl with eye makeup. But one of the conclusions of that GSK paper was that it's not such a great heterocycle for drug development, in the end.
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