MMP-13 selective α-sulfone hydroxamates: a survey of P1' heterocyclic amide isosteres

Bioorg Med Chem Lett. 2011 May 15;21(10):2820-2. doi: 10.1016/j.bmcl.2011.03.099. Epub 2011 Apr 1.

Abstract

Seeking compounds preferentially potent and selective for MMP-13, we reported in the preceding Letter on a series of hydroxamic acids with a flexible benzamide tail groups.(1a) Here, we replace the amide moiety with non-hydrolyzable heterocycles in an effort to improve half-life. We identify a hydroxamate tetrazole 4e that spares MMP-1 and -14, shows >400-fold selectivity versus MMP-8 and >600-fold selectivity versus MMP-2, and has a 4.8 h half-life in rats. X-ray data (1.9 Å) for tetrazole 4c is presented.

MeSH terms

  • Amides / chemical synthesis*
  • Amides / chemistry
  • Animals
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Heterocyclic Compounds / chemical synthesis*
  • Heterocyclic Compounds / chemistry
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / chemistry
  • Matrix Metalloproteinase 13 / chemistry
  • Matrix Metalloproteinase Inhibitors*
  • Models, Molecular
  • Rats
  • Structure-Activity Relationship
  • Substrate Specificity
  • Sulfones / chemical synthesis*
  • Sulfones / chemistry

Substances

  • Amides
  • Enzyme Inhibitors
  • Heterocyclic Compounds
  • Hydroxamic Acids
  • Matrix Metalloproteinase Inhibitors
  • Sulfones
  • Matrix Metalloproteinase 13