Synthesis and cell-based activity of a potent and selective protein tyrosine phosphatase 1B inhibitor prodrug

Irene G. Boutselis, Xiao Yu, Zhong Yin Zhang, Richard F. Borch

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Our laboratory recently reported the development of novel prodrug chemistry for the intracellular delivery of phosphotyrosine mimetics. This chemistry has now been adapted for the synthesis of a prodrug that delivers the nonhydrolyzable difluoromethylphosphonate moiety intracellularly. Activation of the prodrug generates a difluoromethylphosphonamidate anion that undergoes subsequent cyclization and hydrolysis with a t1/2 = 44 min. A highly potent and selective inhibitor of protein tyrosine phosphatase 1B (PTP1B) with a nanomolar Ki has been reported, but this bis(difluoromethylphosphonate) lacks potential utility due to its exceedingly low membrane permeability at physiological pH. A prodrug of this inhibitor has been synthesized and evaluated in a cell-based assay. The prodrug exhibits nanomolar PTP1B inhibitory activity in this assay, confirming the efficacy of intracellular phosphonate delivery using this prodrug approach.

Original languageEnglish (US)
Pages (from-to)856-864
Number of pages9
JournalJournal of Medicinal Chemistry
Volume50
Issue number4
DOIs
StatePublished - Feb 22 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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