| Literature DB >> 30344914 |
Pamela A Haile1, Linda N Casillas1, Michael J Bury1, John F Mehlmann1, Robert Singhaus1, Adam K Charnley1, Terry V Hughes1, Michael P DeMartino1, Gren Z Wang1, Joseph J Romano1, Xiaoyang Dong1, Nikolay V Plotnikov1, Ami S Lakdawala1, Maire A Convery2, Bartholomew J Votta1, David B Lipshutz1, Biva M Desai1, Barbara Swift1, Carol A Capriotti1, Scott B Berger1, Mukesh K Mahajan1, Michael A Reilly1, Elizabeth J Rivera1, Helen H Sun1, Rakesh Nagilla1, Carol LePage1, Michael T Ouellette1, Rachel D Totoritis1, Brian T Donovan1, Barry S Brown1, Khuram W Chaudhary1, Peter J Gough1, John Bertin1, Robert W Marquis1.
Abstract
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 GSK583 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 7, 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 μM).Entities:
Year: 2018 PMID： 30344914 PMCID： PMC6187414 DOI： 10.1021/acsmedchemlett.8b00344
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345