1241947-08-9Relevant articles and documents
Diazinones as P2 replacements for pyrazole-based cathepsin S inhibitors
Ameriks, Michael K.,Bembenek, Scott D.,Burdett, Matthew T.,Choong, Ingrid C.,Edwards, James P.,Gebauer, Damara,Gu, Yin,Karlsson, Lars,Purkey, Hans E.,Staker, Bart L.,Sun, Siquan,Thurmond, Robin L.,Zhu, Jian
scheme or table, p. 4060 - 4064 (2010/08/07)
A pyridazin-4-one fragment 4 (hCatS IC50 = 170 μM) 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 IC50 = 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 IC50 = 60 nM) and 27 (hCatS IC50 = 40 nM).