Further evaluation of novel structural modifications to scaffolds that engender PLD isoform selective inhibition.

This Letter describes the on-going SAR efforts based on two scaffolds, a PLD1-biased piperidinyl benzimidazolone and a PLD2-biased piperidinyl triazaspirone, with the goal of enhancing PLD inhibitory potency and isoform selectivity. Here, we found that addition of an α-methyl moiety within the PLD2-biased piperidinyl triazaspirone scaffold abolished PLD2 preference, while the incorporation of substituents onto the piperidine moiety of the PLD1-biased piperidinyl benzimidazolone, or replacement with a bioisosteric [3.3.0] core, generally retained PLD1 preference, but at diminished significance. The SAR uncovered within these two allosteric PLD inhibitor series further highlights the inherent challenges of developing isoform selective PLD inhibitors.