Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part I: Impact of alternative halogenated privileged structures for PLD1 specificity

Bioorg Med Chem Lett. 2009 Apr 1;19(7):1916-20. doi: 10.1016/j.bmcl.2009.02.057. Epub 2009 Feb 20.

Abstract

This Letter describes the synthesis and structure-activity-relationships (SAR) of isoform-selective PLD inhibitors. By virtue of the installation of alternative halogenated piperidinyl benzimidazolone privileged structures, in combination with a key (S)-methyl group, novel PLD inhibitors with low nM potency and unprecedented levels of PLD1 isoform selectivity (approximately 1700-fold) over PLD2 were developed.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology
  • Cell Line
  • Domperidone / analogs & derivatives*
  • Domperidone / chemical synthesis
  • Domperidone / chemistry
  • Domperidone / pharmacology
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Halogenation
  • Humans
  • Phospholipase D / antagonists & inhibitors*
  • Phospholipase D / metabolism
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • Benzimidazoles
  • Enzyme Inhibitors
  • Protein Isoforms
  • benzimidazolone
  • Domperidone
  • Phospholipase D
  • phospholipase D1