Discovery and SAR of novel pyrazole-based thioethers as cathepsin S inhibitors: Part 1

A series of pyrazole-based thioethers were prepared and found to be potent cathepsin S inhibitors. A crystal structure of 13 suggests that the thioether moiety may bind to the S3 pocket of the enzyme. Additional optimization led to the discovery of aminoethylthioethers with improved enzymatic activi...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2010-04, Vol.20 (7), p.2370-2374
Main Authors: Lee-Dutra, Alice, Wiener, Danielle K., Arienti, Kristen L., Liu, Jing, Mani, Neelakandha, Ameriks, Michael K., Axe, Frank U., Gebauer, Damara, Desai, Pragnya J., Nguyen, Steven, Randal, Mike, Thurmond, Robin L., Sun, Siquan, Karlsson, Lars, Edwards, James P., Jones, Todd K., Grice, Cheryl A.
Format: Article
Language:English
Subjects:
Binding Sites
Biological and medical sciences
Cathepsin
Cathepsins - antagonists & inhibitors
Cathepsins - chemistry
Cathepsins - metabolism
Cell Line
Crystallography, X-Ray
Humans
Immunomodulators
Medical sciences
Models, Molecular
Pharmacology. Drug treatments
Protease
Protease Inhibitors - chemistry
Protease Inhibitors - pharmacology
Pyrazoles - chemistry
Pyrazoles - pharmacology
Structure-Activity Relationship
Sulfides - chemistry
Sulfides - pharmacology
Thioether
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Summary:A series of pyrazole-based thioethers were prepared and found to be potent cathepsin S inhibitors. A crystal structure of 13 suggests that the thioether moiety may bind to the S3 pocket of the enzyme. Additional optimization led to the discovery of aminoethylthioethers with improved enzymatic activity and submicromolar cellular potency.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2010.01.108