4.5 Article

Diazinones as P2 replacements for pyrazole-based cathepsin S inhibitors

Journal

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 20, Issue 14, Pages 4060-4064

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2010.05.086

Keywords

Cathepsin; Protease; Tethering; X-ray crystallography; Fragment-based screening

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A pyridazin-4-one fragment 4 (hCatS IC(50) = 170 mu M) 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). (C) 2010 Elsevier Ltd. All rights reserved.

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