There are some groups of compounds that seem to have a curse on them. They show up in drug screening, they have activity that’s often too good to ignore, but hardly anyone can manage to turn one of them into a drug.
Trifluoromethyl ketones are one example of this. They’re classic inhibitors of proteases, especially serine proteases, and of other enzymes that depend on a serine in their active site. That’s because that ketone really isn’t much of a ketone – the fluorines make the carbon rather unhappy when it’s in that state, electron-poor and ready to pick up a nucleophile and go tetrahedral again. Trifluoromethyl ketones are generally seen in their hydrated state, unless you take care to dry them out, and they’ll work an active-site serine OH into their scheme as well. So you end up with a covalent inhibitor, but a reversible one – the activity comes on slowly, and the compound comes off slowly, too. That trick can work with cysteine nucleophiles, and the hydrate form is also known to coordinate with active-site zinc atoms – so it’s no surprise that the enzyme inhibition literature on these things is mighty extensive: proteases, lipases, esterases, deacetylases, the list goes on for a while.
But although several of these have gone into the clinic over the years, I can’t think of one that’s make it all the way to the market (I’d be glad to hear of any that I’ve overlooked). The best guess is that this isn’t the fault of the functional group, but of the targets it’s been applied to. Some of these enzymes just haven’t panned out, so perhaps the trifluoromethyl ketone awaits its day in the sun.
Another group of this sort is the hydroxamic acid. Its strength is its coordination to zinc atoms, so you see it all over the place in the metallaloprotease literature, and in other zinc-y fields like histone deacetylases. And in vitro, it hardly has a peer. I’ve seen list after list in the literature comparing various zinc-binding head groups, and likely as not, the hydroxamic acid sets the standard every time.
But the reason you see those lists is that people are trying to find something that’ll work other than a hydroxamic acid. There are numerous complaints, ranging from “hydroxylamine is explosive on large scale, you know” and “they’re a pain to make reproducibly” through “they have ugly PK in the animal models” all the way up to “they’re toxic” and “how many of them have ever made it through the clinic?”. How much merit each of these have can be debated, but all together they make an unpleasant picture.
In this case, though, I do know of one that’s made it - SAHA (Zolinza, vorinostat). That one came out of a long-term academic project involving Paul Marks at Sloan-Kettering and Ron Breslow's lab at Columbia, and is one of the not-so-numerous examples of drugs that have made it from the university to the marketplace. Merck signed up to do the clinical and regulatory lifting on this one, and it's now marketed for cutaneous T-cell lymphoma.
So it is possible to get a hydroxamic acid through. "Well, yeah," say the voices, "for cancer, sure. Home of the world's only boronic acid-containing drug. Home, if you really want to get down to it, of nitrogen mustards and God knows what else. Cancer." And it's true that the standards are a bit more relaxed there. I wouldn't necessarily want to give someone a hydoxamic acid every day for the rest of their life, true - the things coordinate iron, for one thing, which isn't always good. But there are other fields where short-term therapy makes sense, and we probably haven't seen the last of this functional group, either.