Development of a phosphatase-resistant, l-tyrosine derived LPA1/LPA3 dual antagonist

James E. East, Karen M. Carter, Perry C. Kennedy, Nancy A. Schulte, Myron L. Toews, Kevin R. Lynch, Timothy L. MacDonald

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Lysophosphatidic acid (LPA) is a bioactive compound that has gained attention due to its role in neoplastic diseases. Our group has developed a potent dual LPA1/LPA3 receptor antagonist, VPC51098 (LPA1 IC50 = 84 nM, LPA1 IC50 = 48 nM) that contained a labile phosphate head group. This lability has impaired our evaluation of our scaffold of LPA receptor antagonists in vivo. We wished to replace the phosphate with a potentially more stable head group while retaining potency at both LPA1 and LPA3 to facilitate future in vivo studies. We tested in vitro potency of all head groups including α-methylene, α-fluoromethylene, α-hydroxymethylene; vinyl phosphonates; α-fluoro vinyl phosphonates. The most potent compound was found to be a low micromolar inhibitor VPC51299 that contained a vinyl phosphonate and possessed a half-life of approximately 90 min in rats when dosed intravenously. Herein, we describe the synthesis and initial biological evaluation of these compounds.

Original languageEnglish (US)
Pages (from-to)325-330
Number of pages6
Issue number4
StatePublished - Apr 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

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