Phenoxyphenyl sulfone N-formylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors

J Med Chem. 2002 Jan 3;45(1):219-32. doi: 10.1021/jm0103920.

Abstract

A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Biological Availability
  • Cell Line
  • Formamides / chemical synthesis*
  • Formamides / chemistry
  • Formamides / pharmacokinetics
  • Formamides / pharmacology
  • Hydroxylamines / chemical synthesis*
  • Hydroxylamines / chemistry
  • Hydroxylamines / pharmacokinetics
  • Hydroxylamines / pharmacology
  • Macaca fascicularis
  • Matrix Metalloproteinase Inhibitors
  • Metalloendopeptidases / antagonists & inhibitors*
  • Mice
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacokinetics
  • Protease Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Formamides
  • Hydroxylamines
  • Matrix Metalloproteinase Inhibitors
  • N-(1-(2,2-dimethyl-1,3-dioxol-4-yl)-2-((4,4-(trifluoromethoxyphenoxy)phenyl)sulfonyl)ethyl)-N-hydroxyformamide
  • Protease Inhibitors
  • Tumor Necrosis Factor-alpha
  • Metalloendopeptidases