Synthesis and pharmacological evaluation of second-generation phosphatidic acid derivatives as lysophosphatidic acid receptor ligands

Bioorg Med Chem Lett. 2006 Feb;16(3):633-40. doi: 10.1016/j.bmcl.2005.10.031. Epub 2005 Nov 2.


Short-chain phosphatidic acid derivatives, dioctanoyl glycerol pyrophosphate (DGPP 8:0, 1) and phosphatidic acid 8:0 (PA 8:0, 2), were previously identified as subtype-selective LPA(1) and LPA(3) receptor antagonists. Recently, we reported that the replacement of the phosphate headgroup by thiophosphate in a series of fatty alcohol phosphates (FAP) improves agonist as well as antagonist activities at LPA GPCR. Here, we report the synthesis of stereoisomers of PA 8:0 analogs and their biological evaluation at LPA GPCR, PPARgamma, and ATX. The results indicate that LPA receptors stereoselectively interact with glycerol backbone modified ligands. We observed entirely stereospecific responses by dioctyl PA 8:0 compounds, in which (R)-isomers were found to be agonists and (S)-isomers were antagonists of LPA GPCR. From this series, we identified compound 13b as the most potent LPA(3) receptor subtype-selective agonist (EC(50)=3 nM), and 8b as a potent and selective LPA(3) receptor antagonist (K(i)=5 nM) and inhibitor of ATX (IC(50)=600 nM). Serinediamide phosphate 19b was identified as an LPA(3) receptor specific antagonist with no effect on LPA(1), LPA(2), and PPARgamma.

Publication types

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

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Ligands
  • Models, Molecular
  • Multienzyme Complexes / metabolism
  • PPAR gamma / metabolism
  • Phosphates / chemistry
  • Phosphatidic Acids / chemical synthesis*
  • Phosphatidic Acids / pharmacology
  • Phosphodiesterase Inhibitors / chemical synthesis*
  • Phosphodiesterase Inhibitors / pharmacology
  • Rats
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Lysophosphatidic Acid / agonists*
  • Receptors, Lysophosphatidic Acid / antagonists & inhibitors*
  • Stereoisomerism


  • Ligands
  • Multienzyme Complexes
  • PPAR gamma
  • Phosphates
  • Phosphatidic Acids
  • Phosphodiesterase Inhibitors
  • Receptors, G-Protein-Coupled
  • Receptors, Lysophosphatidic Acid