4-Amino-2-cyanopyrimidines: Novel Scaffold for Nonpeptidic Cathepsin S Inhibitors

Bioorg Med Chem Lett. 2008 Aug 15;18(16):4642-6. doi: 10.1016/j.bmcl.2008.07.011. Epub 2008 Jul 10.

Abstract

We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selective inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity toward cathepsin S along with promising pharmacokinetic and physicochemical properties. The key structural features of the inhibitors consist of a combination of a spiro[2.5]oct-6-ylmethylamine P2 group at the 4-position, a small or polar P3 group at the 5-position and/or a polar group at the 6-position of the pyrimidine.

MeSH terms

  • Animals
  • Cathepsins / antagonists & inhibitors*
  • Chemistry, Pharmaceutical / methods*
  • Cysteine Proteinase Inhibitors / chemical synthesis*
  • Cysteine Proteinase Inhibitors / pharmacology
  • Drug Design
  • Humans
  • Inhibitory Concentration 50
  • Male
  • Molecular Conformation
  • Nitriles / chemical synthesis*
  • Nitriles / pharmacology
  • Peptides / chemistry*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins / chemistry
  • Structure-Activity Relationship

Substances

  • Cysteine Proteinase Inhibitors
  • Nitriles
  • Peptides
  • Pyrimidines
  • Recombinant Proteins
  • Cathepsins
  • cathepsin S