Bioorganic & Medicinal Chemistry Letters 2009-04-15

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.

Robert Lavieri, Sarah A Scott, Jana A Lewis, Paige E Selvy, Michelle D Armstrong, H Alex Brown, Craig W Lindsley

Index: Bioorg. Med. Chem. Lett. 19 , 2240-3, (2009)

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Abstract

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.