Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10594936 | Bioorganic & Medicinal Chemistry Letters | 2010 | 5 Pages |
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).
Related Topics
Physical Sciences and Engineering
Chemistry
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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,