Synthesis and structure-activity relationship of N-substituted 4-arylsulfonylpiperidine-4-hydroxamic acids as novel, orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis

J Med Chem. 2003 Jun 5;46(12):2376-96. doi: 10.1021/jm0205550.

Abstract

The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. In our preceding paper, we have reported on a series of novel and orally active N-hydroxy-alpha-phenylsulfonylacetamide derivatives. However, these compounds had two drawbacks (moderate selectivity and chirality issues). To circumvent these two problems, a series of novel and orally active N-substituted 4-benzenesulfonylpiperidine-4-carboxylic acid hydroxyamide derivatives have been synthesized. The present paper deals with the synthesis and SAR of these compounds. Among the several compounds synthesized, derivative 55 turned out to be a potent, selective, and an orally active MMP inhibitor in the clinically relevant advanced rabbit osteoarthritis model. Detailed pharmacokinetics and metabolism data are described.

MeSH terms

  • ADAM Proteins
  • ADAM17 Protein
  • Administration, Oral
  • Animals
  • Binding Sites
  • Biological Assay
  • Cartilage / drug effects
  • Cartilage / enzymology
  • Cattle
  • Crystallography, X-Ray
  • Dialysis
  • Dogs
  • Haplorhini
  • Humans
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / pharmacokinetics
  • Hydroxamic Acids / pharmacology
  • Male
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase Inhibitors*
  • Matrix Metalloproteinases / chemistry
  • Metalloendopeptidases / antagonists & inhibitors
  • Mice
  • Models, Molecular
  • Osteoarthritis / drug therapy*
  • Piperidines / chemical synthesis*
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacokinetics
  • Protease Inhibitors / pharmacology
  • Rabbits
  • Rats
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis*
  • Sulfones / pharmacokinetics
  • Sulfones / pharmacology

Substances

  • 1-benzyl-4-(4-(4-chlorophenoxy)benzenesulfonyl)piperidine-4-carboxylic acid
  • Hydroxamic Acids
  • Matrix Metalloproteinase Inhibitors
  • Piperidines
  • Protease Inhibitors
  • Sulfones
  • ADAM Proteins
  • MMP13 protein, human
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinases
  • Metalloendopeptidases
  • Mmp13 protein, mouse
  • Mmp13 protein, rat
  • ADAM17 Protein