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Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors.

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.

SUBMITTER: Haffner CD

PROVIDER: S-EPMC6862347 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors.

Haffner Curt D CD Charnley Adam K AK Aquino Christopher J CJ Casillas Linda L Convery Máire A MA Cox Julie A JA Elban Mark A MA Goodwin Nicole C NC Gough Peter J PJ Haile Pamela A PA Hughes Terry V TV Knapp-Reed Beth B Kreatsoulas Constantine C Lakdawala Ami S AS Li Huijie H Lian Yiqian Y Lipshutz David D Mehlmann John F JF Ouellette Michael M Romano Joseph J Shewchuk Lisa L Shu Arthur A Votta Bartholomew J BJ Zhou Huiqiang H Bertin John J Marquis Robert W RW

ACS medicinal chemistry letters 20191011 11

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 <b>11 ...[more]

PMID: 31749904

Dataset Information

Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors.

Publications

Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors.

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