Alpha,Beta-cyclic-beta-benzamido hydroxamic acids: Novel oxaspiro[4.4]nonane templates for the discovery of potent, selective, orally bioavailable inhibitors of tumor necrosis factor-alpha converting enzyme (TACE)

Bioorg Med Chem Lett. 2008 Feb 15;18(4):1288-92. doi: 10.1016/j.bmcl.2008.01.030. Epub 2008 Jan 11.

Abstract

Two novel oxaspiro[4.4]nonane beta-benzamido hydroxamic scaffolds have been synthesized in enantio- and diasteriomerically pure form. These templates proved to be exceptional platforms that have led to the discovery of potent inhibitors of TACE that are active in a cellular assay measuring suppression of LPS-induced TNF-alpha. Furthermore, these inhibitors are selective against related MMPs, demonstrate permeability in a Caco-2 assay, and display good oral bioavailability.

MeSH terms

  • ADAM Proteins / antagonists & inhibitors*
  • ADAM17 Protein
  • Administration, Oral
  • Alkanes / chemical synthesis
  • Alkanes / chemistry*
  • Alkanes / pharmacokinetics
  • Alkanes / pharmacology
  • Animals
  • Biological Availability
  • Caco-2 Cells
  • Humans
  • Hydroxamic Acids / chemical synthesis
  • Hydroxamic Acids / chemistry*
  • Hydroxamic Acids / pharmacokinetics
  • Hydroxamic Acids / pharmacology*
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinases / metabolism
  • Models, Molecular
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacokinetics
  • Protease Inhibitors / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry*
  • Spiro Compounds / pharmacokinetics
  • Spiro Compounds / pharmacology

Substances

  • Alkanes
  • Hydroxamic Acids
  • Matrix Metalloproteinase Inhibitors
  • Protease Inhibitors
  • Spiro Compounds
  • ADAM Proteins
  • Matrix Metalloproteinases
  • ADAM17 Protein
  • ADAM17 protein, human
  • Adam17 protein, rat
  • nonane