70695-78-2Relevant academic research and scientific papers
Discovery of cathepsin S inhibitor LY3000328 for the treatment of abdominal aortic aneurysm
Jadhav, Prabhakar K.,Schiffler, Matthew A.,Gavardinas, Kostas,Kim, Euibong J.,Matthews, Donald P.,Staszak, Michael A.,Coffey, D. Scott,Shaw, Bruce W.,Cassidy, Kenneth C.,Brier, Richard A.,Zhang, Yuke,Christie, Robert M.,Matter, William F.,Qing, Keyun,Durbin, Jim D.,Wang, Yong,Deng, Gary G.
supporting information, p. 1138 - 1142 (2014/12/10)
Cathepsin S (Cat S) plays an important role in many pathological conditions, including abdominal aortic aneurysm (AAA). Inhibition of Cat S may provide a new treatment for AAA. To date, several classes of Cat S inhibitors have been reported, many of which form covalent interactions with the active site Cys25. Herein, we report the discovery of a novel series of noncovalent inhibitors of Cat S through a medium-throughput focused cassette screen and the optimization of the resulting hits. Structure-based optimization efforts led to Cat S inhibitors such as 5 and 9 with greatly improved potency and drug disposition properties. This series of compounds binds to the S2 and S3 subsites without interacting with the active site Cys25. On the basis of in vitro potency, selectivity, and efficacy in a CaCl2-induced AAA in vivo model, 5 (LY3000328) was selected for clinical development.
Cathepsin S Inhibitor Compounds
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Page/Page column 8, (2012/04/23)
The present invention provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof. Also, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable diluent or carrier. The present invention further provides methods for treating abdominal aortic aneurysm, plaque instability, atherosclerosis, or autoimmune disorders such as rheumatoid arthritis, psoriasis, and lupus comprising administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
