Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors.
Basic Information
ID: ALA4312039
Journal: ACS Med Chem Lett
Title: Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors.
Authors: Haffner CD, Charnley AK, Aquino CJ, Casillas L, Convery MA, Cox JA, Elban MA, Goodwin NC, Gough PJ, Haile PA, Hughes TV, Knapp-Reed B, Kreatsoulas C, Lakdawala AS, Li H, Lian Y, Lipshutz D, Mehlmann JF, Ouellette M, Romano J, Shewchuk L, Shu A, Votta BJ, Zhou H, Bertin J, Marquis RW.
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.
CiteXplore: 31749904
DOI: 10.1021/acsmedchemlett.9b00141
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