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

Alice Lee-Dutra; Danielle K Wiener; Kristen L Arienti; Jing Liu; Neelakandha Mani; Michael K Ameriks; Frank U Axe; Damara Gebauer; Pragnya J Desai; Steven Nguyen; Mike Randal; Robin L Thurmond; Siquan Sun; Lars Karlsson; James P Edwards; Todd K Jones; Cheryl A Grice

doi:10.1016/j.bmcl.2010.01.108

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

Bioorg Med Chem Lett. 2010 Apr 1;20(7):2370-4. doi: 10.1016/j.bmcl.2010.01.108. Epub 2010 Jan 28.

Authors

Alice Lee-Dutra¹, Danielle K Wiener, Kristen L Arienti, Jing Liu, Neelakandha Mani, Michael K Ameriks, Frank U Axe, Damara Gebauer, Pragnya J Desai, Steven Nguyen, Mike Randal, Robin L Thurmond, Siquan Sun, Lars Karlsson, James P Edwards, Todd K Jones, Cheryl A Grice

Affiliation

¹ Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA. [email protected]

PMID: 20153648
DOI: 10.1016/j.bmcl.2010.01.108

Abstract

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.

MeSH terms

Binding Sites
Cathepsins / antagonists & inhibitors*
Cathepsins / chemistry
Cathepsins / metabolism*
Cell Line
Crystallography, X-Ray
Humans
Models, Molecular
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology*
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Structure-Activity Relationship
Sulfides / chemistry
Sulfides / pharmacology*

Substances

Protease Inhibitors
Pyrazoles
Sulfides
pyrazole
Cathepsins
cathepsin S