title: 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.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.
authors.forename: Major
authors.initials: M
authors.lastname: Gooyit
authors.forename: Mijoon
authors.initials: M
authors.lastname: Lee
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Schroeder
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ikejiri
authors.forename: Mark A
authors.initials: MA
authors.lastname: Suckow
authors.forename: Shahriar
authors.initials: S
authors.lastname: Mobashery
authors.forename: Mayland
authors.initials: M
authors.lastname: Chang
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D018093:Gelatinases / Q000037:antagonists & inhibitors*; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014867:Water
chemical_list: D000577:Amides; D006573:Heterocyclic Compounds, 1-Ring; C568509:ND 322; D011355:Prodrugs; C429533:SB 3CT compound; D013450:Sulfones; D014867:Water; D001120:Arginine; D018093:Gelatinases