O-phenyl carbamate and phenyl urea thiiranes as selective matrix metalloproteinase-2 inhibitors that cross the blood-brain barrier

J Med Chem. 2013 Oct 24;56(20):8139-50. doi: 10.1021/jm401217d. Epub 2013 Oct 8.

Abstract

Brain metastasis occurs in 20-40% of cancer patients. Treatment is mostly palliative, and the inability of most drugs to penetrate the brain presents one of the greatest challenges in the development of therapeutics for brain metastasis. Matrix metalloproteinase-2 (MMP-2) plays important roles in invasion and vascularization of the central nervous system and represents a potential target for treatment of brain metastasis. Carbonate, O-phenyl carbamate, urea, and N-phenyl carbamate derivatives of SB-3CT, a selective and potent gelatinase inhibitor, were synthesized and evaluated. The O-phenyl carbamate and urea variants were selective and potent inhibitors of MMP-2. Carbamate 5b was metabolized to the potent gelatinase inhibitor 2, which was present at therapeutic concentrations in the brain. In contrast, phenyl urea 6b crossed the blood-brain barrier, however, higher doses would result in therapeutic brain concentrations. Carbamate 5b and urea 6b show potential for intervention of MMP-2-dependent diseases such as brain metastasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Area Under Curve
  • Blood-Brain Barrier / metabolism*
  • Carbamates / chemical synthesis*
  • Carbamates / chemistry
  • Carbamates / pharmacokinetics
  • Heterocyclic Compounds, 1-Ring / chemical synthesis
  • Heterocyclic Compounds, 1-Ring / chemistry
  • Heterocyclic Compounds, 1-Ring / pharmacokinetics
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinase Inhibitors / chemical synthesis*
  • Matrix Metalloproteinase Inhibitors / chemistry
  • Matrix Metalloproteinase Inhibitors / pharmacokinetics
  • Mice
  • Models, Chemical
  • Molecular Structure
  • Phenol / chemistry
  • Phenylurea Compounds / chemical synthesis*
  • Phenylurea Compounds / chemistry
  • Phenylurea Compounds / pharmacokinetics
  • Structure-Activity Relationship
  • Sulfides / chemical synthesis*
  • Sulfides / chemistry
  • Sulfides / pharmacokinetics

Substances

  • 1-ethyl-3-(4-(4-((thiiran-2-ylmethyl)sulfonyl)phenoxy)phenyl)urea
  • 4-(4-((thiiran-2-ylmethyl)sulfonyl)phenoxy)phenyl ethylcarbamate
  • Carbamates
  • Heterocyclic Compounds, 1-Ring
  • Matrix Metalloproteinase Inhibitors
  • Phenylurea Compounds
  • Sulfides
  • Phenol
  • N-phenylurea
  • ethylene sulfide
  • Matrix Metalloproteinase 2