Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin K inhibitors

Bioorg Med Chem Lett. 2010 Mar 1;20(5):1524-7. doi: 10.1016/j.bmcl.2010.01.100. Epub 2010 Jan 25.

Abstract

Morphing structural features of HTS-derived chemotypes led to the discovery of novel 2-cyano-pyrimidine inhibitors of cathepsin K with good pharmacokinetic profiles, for example, compound 20 showed high catK potency (IC(50)=4nM), >580-fold selectivity over catL and catB, and oral bioavailability in the rat of 52%.

MeSH terms

  • Administration, Oral
  • Animals
  • Binding Sites
  • Cathepsin K / antagonists & inhibitors*
  • Cathepsin K / metabolism
  • Cell Line
  • Crystallography, X-Ray
  • Cysteine Proteinase Inhibitors / chemical synthesis
  • Cysteine Proteinase Inhibitors / chemistry*
  • Cysteine Proteinase Inhibitors / pharmacokinetics
  • Drug Design
  • High-Throughput Screening Assays
  • Humans
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • Cysteine Proteinase Inhibitors
  • Pyrimidines
  • Cathepsin K