Ben Cravatt is talking about this work on activity-based protein profiling of serine hydrolase enzymes. That's quite a class to work on - as he says, up to 2% of all the proteins in the body fall into this group, but only half of them have had even the most cursory bit of characterization. Even among the "known" ones, most of their activities are still dark, and only 10% of them have useful pharmacological tools.
He's detailed a compound (PF-3845) that Pfizer found as a screening hit for FAAH, which although it looked benign, turned out to be a covalent inhibitor due to a reactive arylurea. Pfizer, he says, backed off when this mechanism was uncovered - they weren't ready at the time for covalency, but he says that they've loosened up since then. Studying the compound in various tissues, including the brain, showed that it was extremely selective for FAAH.
Another reactive compound, JZL184, is an inhibitor of monoacylglycerol hydrolase (MAGL). Turns out that its carbamate group also reacts with FAAH, but there's a 300-fold window in the potency. The problem is, that's not enough. In mouse models, hitting both enzymes at the same time leads to behavioral problems. Changing the leaving group to a slightly less reactive (and nonaromatic) hexafluoroisopropanol, though, made the compound selective again. I found this quite interesting - most of the time, you'd think that 300x is plenty of room, but apparently not. That doesn't make things any easier, does it?
In response to a question (from me), he says that covalency is what makes this tricky. The half-life of the brain enzymes is some 12 to 14 hours, so by the time the next once-a-day dose comes in, there's still 20 or 30% of the enzyme still shut down, and things get out of hand pretty soon. For a covalent mechanism, he recommends 2000-fold or 5000-fold. On the other hand, he says that when they've had a serine hydrolase-targeted compound, they've never seen it react out of that class (targeting cysteine residues, though, is a very different story). And the covalent mechanism gives you some unique opportunities - for example, deliberate engineering a short half-life, because that might be all you need.