Isoform selective PLD inhibition by novel, chiral 2,8-diazaspiro[4.5]decan-1-one derivatives

[Display omitted] •A novel 2,8-diazaspiro[4.5]decan-1-one core affords enantioselective inhibition of PLD enzymes.•A single chemotype can produce PLD1, PLD2 and dual PLD1/PLD2 inhibitors.•The new series afford improvements in protein binding, predicted clearance and half-life in vivo.•Novelty allowed for the first, and only issued, US patent covering PLD inhibitors. This letter describes the on-going SAR efforts to develop PLD1, PLD2 and dual PLD1/2 inhibitors with improved physiochemical and disposition properties as well as securing intellectual property position. Previous PLD inhibitors, based on a triazaspiro[4.5]decanone core proved to be highly selective PLD2 inhibitors, but with low plasma free fraction (rat, human fu 65 mL/min/kg) and very short half-lives in vivo (t1/2