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

Bioorg Med Chem Lett. 2009 Apr 15;19(8):2240-3. doi: 10.1016/j.bmcl.2009.02.125. Epub 2009 Mar 6.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Phospholipase D / antagonists & inhibitors*
  • Phospholipase D / metabolism
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Isoenzymes
  • phospholipase D2
  • Phospholipase D
  • phospholipase D1