Selective water-soluble gelatinase inhibitor prodrugs.

Abstract

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.

• Authors: Major Gooyit, Mijoon Lee, Valerie A Schroeder, Masahiro Ikejiri, Mark A Suckow, Shahriar Mobashery, Mayland Chang
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 54 Issue 19 Pg. 6676-90 (Oct 13 2011) ISSN: 1520-4804 [Electronic] United States
• PMID: 21866961 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Amides
• Heterocyclic Compounds, 1-Ring
• ND 322
• Prodrugs
• SB 3CT compound
• Sulfones
• Water
• Arginine
• Gelatinases

Topics

• Amides (chemical synthesis, pharmacokinetics, pharmacology)
• Animals
• Arginine (analogs & derivatives, chemical synthesis, pharmacokinetics, pharmacology)
• Gelatinases (antagonists & inhibitors)
• Heterocyclic Compounds, 1-Ring (chemical synthesis, pharmacokinetics, pharmacology)
• Humans
• Hydrolysis
• In Vitro Techniques
• Male
• Mice
• Mice, Inbred C57BL
• Microsomes, Liver (metabolism)
• Mutagenicity Tests
• Prodrugs (chemical synthesis, pharmacokinetics, pharmacology)
• Rats
• Solubility
• Structure-Activity Relationship
• Sulfones (chemical synthesis, pharmacokinetics, pharmacology)
• Water