Further evaluation of novel structural modifications to scaffolds that engender PLD isoform selective inhibition

Bioorg Med Chem Lett. 2014 Dec 15;24(24):5553-5557. doi: 10.1016/j.bmcl.2014.11.017. Epub 2014 Nov 15.

Abstract

This Letter describes the on-going SAR efforts based on two scaffolds, a PLD1-biased piperidinyl benzimidazolone and a PLD2-biased piperidinyl triazaspirone, with the goal of enhancing PLD inhibitory potency and isoform selectivity. Here, we found that addition of an α-methyl moiety within the PLD2-biased piperidinyl triazaspirone scaffold abolished PLD2 preference, while the incorporation of substituents onto the piperidine moiety of the PLD1-biased piperidinyl benzimidazolone, or replacement with a bioisosteric [3.3.0] core, generally retained PLD1 preference, but at diminished significance. The SAR uncovered within these two allosteric PLD inhibitor series further highlights the inherent challenges of developing isoform selective PLD inhibitors.

Keywords: Inhibitors; Isoform; Phosphodiesterase; Phospholipase D (PLD).

Publication types

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

MeSH terms

  • Animals
  • Benzimidazoles / chemistry
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • HEK293 Cells
  • Humans
  • Kinetics
  • Microsomes / metabolism
  • Phospholipase D / antagonists & inhibitors*
  • Phospholipase D / metabolism
  • Piperidines / chemistry
  • Protein Binding
  • Rats
  • Structure-Activity Relationship

Substances

  • Benzimidazoles
  • Enzyme Inhibitors
  • Piperidines
  • benzimidazolone
  • piperidine
  • phospholipase D2
  • Phospholipase D
  • phospholipase D1