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

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Boutselis IG,Yu X,Zhang ZY,Borch RF

doi

10.1021/jm061146x

subject

Has Abstract

pub_date

2007-02-22 00:00:00

pages

856-64

issue

4

eissn

0022-2623

issn

1520-4804

journal_volume

50

pub_type

杂志文章

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