Diazinones as P2 Replacements for Pyrazole-Based Cathepsin S Inhibitors

Bioorg Med Chem Lett. 2010 Jul 15;20(14):4060-4. doi: 10.1016/j.bmcl.2010.05.086. Epub 2010 May 25.


A pyridazin-4-one fragment 4 (hCatS IC(50)=170 microM) discovered through Tethering was modeled into cathepsin S and predicted to overlap in S2 with the tetrahydropyridinepyrazole core of a previously disclosed series of CatS inhibitors. This fragment served as a template to design pyridazin-3-one 12 (hCatS IC(50)=430 nM), which also incorporates P3 and P5 binding elements. A crystal structure of 12 bound to Cys25Ser CatS led to the synthesis of the potent diazinone isomers 22 (hCatS IC(50)=60 nM) and 27 (hCatS IC(50)=40 nM).

MeSH terms

  • Cathepsins / antagonists & inhibitors*
  • Crystallography, X-Ray
  • Models, Molecular
  • Protease Inhibitors / chemistry*
  • Pyrazoles / chemistry*
  • Structure-Activity Relationship


  • Protease Inhibitors
  • Pyrazoles
  • Cathepsins
  • cathepsin S