In the process of developing poly-ADP ribose polymerase (PARP) inhibitors as potential anti-cancer agents, Chungang Gu and co-workers studied how modulating the strength of hydrogen-bond acceptors could be used to optimize the bioavailability of PARP inhibitors. They found that tuning the electronic properties of a key triazole ring was able to simultaneously modulate binding affinity, permeability, and efflux ratio (Figure ). Compound D.15 maintained potency while dramatically increasing permeability and decreasing efflux (Table ), and was selected for further in vivo studies. pK BHX predictions can be used to interpret these experimental results. Compound D.1, the strongest hydrogen-bond acceptor, has pK BHX values of 2.28 and 2.37 on the two triazole nitrogens (Table ). Adding additional fluorines to the compound reduces the basicity of Figure : Glycocosylceramide synthase inhibitors investigated by Roecker and co-workers. The basic oxygen is labeled in green, with the corresponding pK BHX values computed by Rowan nearby. For experimental assay details, refer to Roecker et al. the triazole nitrogens, which makes the compound more permeable and less susceptible to efflux-compound D.15, which has a difluoroethyl group, preserves the activity of the parent compound while dramatically improving its biophysical properties. Surprisingly, moving from difluoroethyl to trifluoromethyl causes a fourfold decrease in EC 50 , a decrease in permeability, and an increase in efflux ratio (Table ), contrary in all three cases to what simple trends based on pK BHX would predict. Activity cliffs like this are not uncommon in chemical structure-activity relationships, illustrating the limitations in using any single descriptor to predict compound performance.