Here’s a caution from a new paper out of Manchester. The group had been synthesizing inhibitors of PARG (poly-ADP ribose glycohydrolase), an enzyme involved in DNA repair. The general chemotype is shown at right, but there are a number of variations. That fluorine is a new addition, though. The corresponding cyclopropylmethyl series came from their earlier paper, but they found that the series wasn’t particularly stable to metabolic oxidation. The major metabolites proved to be the primary sulfonamides in each case, suggesting that oxidation of the cyclopropylmethyl itself (which would be most likely at the methyl carbon) was the problem. Indeed, fluorination as shown increased the microsomal stability substantially (difluorination decreased the affinity for the PARG target itself, and deuteration, interestingly, had no real effect).
So far, so good. But trouble hit when the compounds were dosed in mice – there were obvious signs of toxicity, and deaths at the higher doses. This had never been seen with the earlier compounds, and dosing a fluoromethyl analog that had significantly reduced PARG potency showed the same effects. The trouble was noted at around the five-hour point, and only after oral dosing. Necropsy showed obvious signs of liver damage, which fits with that observation as well.
That all adds up to off-target tox brought on by metabolic activation of the fluoromethylcyclopropyl group. What the active species might be is not clear yet, nor is the specific liver target. But these observations alone are enough to flag that modification as a serious potential problem, which is the whole reason this new paper was published. Monofluoroalkyls can be a little odd – terminal monofluoroalkanes get cleaved down to fluoroacetic acid, for example, which is toxicological bad news. And fluorobenzyls (monofluoromethyl aryls) are reactive as electrophiles, despite the fluorocarbon reputation for stability. But this appears to be something different from either of those cases.
It’s true that this may vary according to the rest of the molecule, but just seeing it show up this strongly in one series is cause for concern. And since cyclopropyl groups and fluorinated methyls are both pretty common motifs in medicinal chemistry, it’s important to realize that the combination could be bad news. A quick Reaxys search of the fluoromethylcyclopropylsulfonamide side chain gave 183 hits, but those are all from two patents filed by the Manchester group themselves. But if you search for the corresponding amide, you also pick up a couple of compounds from Gilead as IRAK-4 inhibitors. The amine is a perfectly reasonable-looking building block, and it would be a good thing if it did not spread through the med-chem literature without people knowing that there may be a red flag attached to it.