Design, synthesis, and biological evaluation of potent thiazine- and thiazepine-based matrix metalloproteinase inhibitors

J Med Chem. 1999 Nov 4;42(22):4547-62. doi: 10.1021/jm990330y.

Abstract

The synthesis and enzyme inhibition data for a series of thiazine- and thiazepine-based matrix metalloproteinase (MMP) inhibitors are described. The thiazine- and thiazepine-based inhibitors were discovered by optimization of hetererocyclic sulfonamide-based inhibitors. The most potent series of inhibitors was obtained by modification of the amino acid D-penicillamine. This amino acid provides a gem-dimethyl group on the thiazine or thiazepine ring which has a dramatic effect on the in vitro potency of this series. In particular, the sulfide 4a and the sulfone 5a were potent, broad-spectrum inhibitors of the MMPs with IC(50)'s against MMP-1 of 0.8 and 1.9 nM, respectively. The binding mode of this novel thiazepine-based series of MMP inhibitors was established based on X-ray crystallography of the complex of stromelysin and 4a.

MeSH terms

  • Crystallography, X-Ray
  • Cyclic S-Oxides / chemical synthesis*
  • Cyclic S-Oxides / chemistry
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Metalloendopeptidases / antagonists & inhibitors*
  • Models, Molecular
  • Structure-Activity Relationship
  • Thiazepines / chemical synthesis*
  • Thiazepines / chemistry
  • Thiazines / chemical synthesis*
  • Thiazines / chemistry

Substances

  • Cyclic S-Oxides
  • Enzyme Inhibitors
  • N-hydroxy-4-((4--methoxyphenyl)sulfonyl)-2,2-dimethylhexahydro-1,4-thiazepine-3-carboxamide 1,1-dioxide
  • N-hydroxy-4-((4-methoxyphenyl)sulfonyl)-2,2-dimethylhexahydro-1,4-thiazepine-3-carboxamide
  • Thiazepines
  • Thiazines
  • Metalloendopeptidases