Diazinones as P2 replacements for pyrazole-based cathepsin S inhibitors

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).