Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part II. Identification of the 1,3,8-triazaspiro[4,5]decan-4-one privileged structure that engenders PLD2 selectivity

This Letter describes the synthesis and structure–activity relationships (SAR) of isoform-selective PLD inhibitors. By virtue of the installation of a 1,3,8-triazaspiro[4,5]decan-4-one privileged structure, PLD inhibitors with nanomolar potency and an unprecedented 40-fold selectivity for PLD2 over PLD1 were developed. Interestingly, SAR for this diverged from our earlier efforts, and dual PLD1/2 inhibitors were also discovered within this series.

Graphical abstractThe synthesis and SAR of isoform-selective PLD inhibitors is described. By virtue of the installation of the 1,3,8-triazaspiro[4,5]decan-4-one privileged structure, inhibitors with up to an unprecedented 40-fold selectivity for PLD2 over PLD1 were developed. Interestingly, SAR for this series diverged considerably from earlier efforts, and also provided potent dual PLD1/2 inhibitors.Figure optionsDownload full-size imageDownload as PowerPoint slide