Selective water-soluble gelatinase inhibitor prodrugs

Major Gooyit, Mijoon Lee, Valerie A. Schroeder, Masahiro Ikejiri, Mark A. Suckow, Shahriar Mobashery, Mayland Chang

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


SB-3CT (1), a selective and potent thiirane-based gelatinase inhibitor, is effective in animal models of cancer metastasis and stroke; however, it is limited by poor aqueous solubility and extensive metabolism. We addressed these issues by blocking the primary site of metabolism and capitalizing on a prodrug strategy to achieve >5000-fold increased solubility. The amide prodrugs were quantitatively hydrolyzed in human blood to a potent gelatinase inhibitor, ND-322 (3). The arginyl amide prodrug (ND-478, 5d) was metabolically stable in mouse, rat, and human liver microsomes. Both 5d and 3 were nonmutagenic in the Ames II mutagenicity assay. The prodrug 5d showed moderate clearance of 0.0582 L/min/kg, remained mostly in the extracellular fluid compartment (Vd = 0.0978 L/kg), and had a terminal half-life of >4 h. The prodrug 5d had superior pharmacokinetic properties than those of 3, making the thiirane class of selective gelatinase inhibitors suitable for intravenous administration in the treatment of acute gelatinase-dependent diseases.

Original languageEnglish
Pages (from-to)6676-6690
Number of pages15
JournalJournal of Medicinal Chemistry
Issue number19
StatePublished - Oct 13 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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