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Diazinones as P2 replacements for pyrazole-based cathepsin S inhibitors |
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| Authors: | Michael K Ameriks Scott D Bembenek Matthew T Burdett Ingrid C Choong James P Edwards Damara Gebauer Yin Gu Lars Karlsson Hans E Purkey Bart L Staker Siquan Sun Robin L Thurmond Jian Zhu |
| Institution: | 1. Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA;2. Sunesis Pharmaceuticals, 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA;3. deCODE Biostructures, Inc., 7869 Northeast Day Road West, Bainbridge Island, WA 98110, USA |
| Abstract: | 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). |
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