title: Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm.
abstract: 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.
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center , Indianapolis, Indiana 46285, United States.
authors.forename: Prabhakar K
authors.initials: PK
authors.lastname: Jadhav
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center , Indianapolis, Indiana 46285, United States.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Schiffler
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center , Indianapolis, Indiana 46285, United States.
authors.forename: Kostas
authors.initials: K
authors.lastname: Gavardinas
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center , Indianapolis, Indiana 46285, United States.
authors.forename: Euibong J
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center , Indianapolis, Indiana 46285, United States.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Matthews
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center , Indianapolis, Indiana 46285, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Staszak
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center , Indianapolis, Indiana 46285, United States.
authors.forename: D Scott
authors.initials: DS
authors.lastname: Coffey
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center , Indianapolis, Indiana 46285, United States.
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Shaw
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center , Indianapolis, Indiana 46285, United States.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Cassidy
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center , Indianapolis, Indiana 46285, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Brier
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center , Indianapolis, Indiana 46285, United States.
authors.forename: Yuke
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center , Indianapolis, Indiana 46285, United States.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Christie
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center , Indianapolis, Indiana 46285, United States.
authors.forename: William F
authors.initials: WF
authors.lastname: Matter
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center , Indianapolis, Indiana 46285, United States.
authors.forename: Keyun
authors.initials: K
authors.lastname: Qing
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center , Indianapolis, Indiana 46285, United States.
authors.forename: Jim D
authors.initials: JD
authors.lastname: Durbin
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center , Indianapolis, Indiana 46285, United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center , Indianapolis, Indiana 46285, United States.
authors.forename: Gary G
authors.initials: GG
authors.lastname: Deng
keywords: Cathepsin; abdominal aortic aneurysm; development candidate; noncovalent