4p6e

Publication Abstract from PubMed

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.

Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm.,Jadhav PK, Schiffler MA, Gavardinas K, Kim EJ, Matthews DP, Staszak MA, Coffey DS, Shaw BW, Cassidy KC, Brier RA, Zhang Y, Christie RM, Matter WF, Qing K, Durbin JD, Wang Y, Deng GG ACS Med Chem Lett. 2014 Aug 27;5(10):1138-42. doi: 10.1021/ml500283g. eCollection, 2014 Oct 9. PMID:25313327^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.