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 Lee Toews, Kevin R. Lynch, Timothy L. MacDonald

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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
JournalMedChemComm
Volume2
Issue number4
DOIs
StatePublished - Apr 1 2011

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Lysophosphatidic Acid Receptors
Organophosphonates
Phosphoric Monoester Hydrolases
Tyrosine
Inhibitory Concentration 50
Phosphates
Scaffolds
Half-Life
Rats
Head

ASJC Scopus subject areas

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

Cite this

East, J. E., Carter, K. M., Kennedy, P. C., Schulte, N. A., Toews, M. L., Lynch, K. R., & MacDonald, T. L. (2011). Development of a phosphatase-resistant, l-tyrosine derived LPA1/LPA3 dual antagonist. MedChemComm, 2(4), 325-330. https://doi.org/10.1039/c0md00273a

Development of a phosphatase-resistant, l-tyrosine derived LPA1/LPA3 dual antagonist. / East, James E.; Carter, Karen M.; Kennedy, Perry C.; Schulte, Nancy A.; Toews, Myron Lee; Lynch, Kevin R.; MacDonald, Timothy L.

In: MedChemComm, Vol. 2, No. 4, 01.04.2011, p. 325-330.

Research output: Contribution to journalArticle

East, JE, Carter, KM, Kennedy, PC, Schulte, NA, Toews, ML, Lynch, KR & MacDonald, TL 2011, 'Development of a phosphatase-resistant, l-tyrosine derived LPA1/LPA3 dual antagonist', MedChemComm, vol. 2, no. 4, pp. 325-330. https://doi.org/10.1039/c0md00273a
East, James E. ; Carter, Karen M. ; Kennedy, Perry C. ; Schulte, Nancy A. ; Toews, Myron Lee ; Lynch, Kevin R. ; MacDonald, Timothy L. / Development of a phosphatase-resistant, l-tyrosine derived LPA1/LPA3 dual antagonist. In: MedChemComm. 2011 ; Vol. 2, No. 4. pp. 325-330.
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