Synthesis, structure-activity relationships, and biological evaluation of fatty alcohol phosphates as lysophosphatidic acid receptor ligands, activators of PPARγ, and inhibitors of autotaxin

Gangadhar G. Durgam, Tamas Virag, Michelle D. Walker, Ryoko Tsukahara, Satoshi Yasuda, Karoly Liliom, Laurens A. Van Meeteren, Wouter H. Moolenaar, Nicole Wilke, Wolfgang Siess, Gabor Tigyi, Duane D. Miller

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

We previously reported that fatty alcohol phosphates (FAP) represent a minimal pharmacophore required to interact with lysophosphatidic acid (LPA) receptors. To improve the activity of the first-generation saturated FAP series, a structure-activity relationship (SAR) study was carried out that includes modifications to the headgroup and alkyl side chain of the FAP pharmacophore. A series of unsaturated (C10-C18) FAP, headgroup-modified hydrolytically stable saturated (C10-C18) alkyl phosphonates, and saturated and unsaturated (C10-C18) thiophosphate analogues were synthesized and evaluated for activity in RH7777 cells transfected with individual LPA1-3 receptors, in PC-3 cells and in human platelets that endogenously express all three isoforms. In this series we identified several LPA1- and LPA3-selective antagonists with IC50 values in the nanomolar range. Oleoyl-thiophosphate (15g) was shown to be a panagonist, whereas tetradecyl-phosphonate (16c) was identified as a pan-antagonist. These compounds were also tested for the ability to activate the transcription factor PPARγ, an intracellular receptor for LPA, in CV1 cells transfected with the PPRE-Acox-Rluc reporter gene. All the FAP tested, along with the previously reported LPA GPCR antagonists dioctanoyl glycerol pyrophosphate (2), Ki16425 (6), and the agonist OMPT (3), were activators of PPARγ. The pan-agonist oleoyl-thiophosphate (15g) and pan-antagonist tetradecyl-phosphonate (16c) mimicked LPA in inhibiting autotaxin, a secreted lysophospholipase D that produces LPA in biological fluids.

Original languageEnglish
Pages (from-to)4919-4930
Number of pages12
JournalJournal of Medicinal Chemistry
Volume48
Issue number15
DOIs
Publication statusPublished - Jul 28 2005

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Synthesis, structure-activity relationships, and biological evaluation of fatty alcohol phosphates as lysophosphatidic acid receptor ligands, activators of PPARγ, and inhibitors of autotaxin'. Together they form a unique fingerprint.

  • Cite this

    Durgam, G. G., Virag, T., Walker, M. D., Tsukahara, R., Yasuda, S., Liliom, K., Van Meeteren, L. A., Moolenaar, W. H., Wilke, N., Siess, W., Tigyi, G., & Miller, D. D. (2005). Synthesis, structure-activity relationships, and biological evaluation of fatty alcohol phosphates as lysophosphatidic acid receptor ligands, activators of PPARγ, and inhibitors of autotaxin. Journal of Medicinal Chemistry, 48(15), 4919-4930. https://doi.org/10.1021/jm049609r