biostudies-literatureUnknown9(10)Haile PARIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor <b>GSK583</b> and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compound was valuable in validating the biological pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog. Herein, we detail our efforts to improve both this off-target liability as well as the PK/PD profile of this series of inhibitors through modulation of lipophilicity and strengthening hinge binding ability. These efforts have led to inhibitor <b>7</b>, which possesses high binding affinity for the ATP pocket of RIP2 (IC₅₀ = 1 nM) and inhibition of downstream cytokine production in human whole blood (IC₅₀ = 10 nM) with reduced hERG activity (14 ?M).ACS medicinal chemistry letters1039-1044https://www.ebi.ac.uk/biostudies/studies/S-EPMC6187414biostudies-literatureIdentification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel.PMC6187414Convery MABerger SBRivera EJBury MJDong XGough PJCharnley AKDeMartino MPTotoritis RDBertin JMehlmann JFWang GZMahajan MKLePage CHaile PAMarquis RWHughes TVNagilla RChaudhary KWCasillas LNPlotnikov NVBrown BSLakdawala ASLipshutz DBCapriotti CAOuellette MTSun HHSinghaus RRomano JJDonovan BTReilly MADesai BMSwift BVotta BJfalseIdentification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel.RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor <b>GSK583</b> and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compound was valuable in validating the biological pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog. Herein, we detail our efforts to improve both this off-target liability as well as the PK/PD profile of this series of inhibitors through modulation of lipophilicity and strengthening hinge binding ability. These efforts have led to inhibitor <b>7</b>, which possesses high binding affinity for the ATP pocket of RIP2 (IC₅₀ = 1 nM) and inhibition of downstream cytokine production in human whole blood (IC₅₀ = 10 nM) with reduced hERG activity (14 ?M).2018-01-01T00:00:00Z2018 Oct2021-02-21T05:42:13Z2019-10-16T07:00:55ZS-EPMC61874143034491410.1021/acsmedchemlett.8b00344