| Literature DB >> 31749904 |
Curt D Haffner1, Adam K Charnley1, Christopher J Aquino1,2, Linda Casillas1, Máire A Convery2, Julie A Cox1, Mark A Elban1, Nicole C Goodwin1, Peter J Gough1, Pamela A Haile1, Terry V Hughes1,2, Beth Knapp-Reed1, Constantine Kreatsoulas1, Ami S Lakdawala1, Huijie Li1, Yiqian Lian1, David Lipshutz1, John F Mehlmann1, Michael Ouellette1, Joseph Romano1, Lisa Shewchuk1, Arthur Shu1, Bartholomew J Votta1, Huiqiang Zhou1, John Bertin1, Robert W Marquis1.
Abstract
Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallography was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a selective and potent inhibitor of RIP2 and will allow for a more detailed investigation of RIP2 inhibition as a therapeutic target for autoinflammatory disorders.Entities:
Year: 2019 PMID： 31749904 PMCID： PMC6862347 DOI： 10.1021/acsmedchemlett.9b00141
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345