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

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

  • ACS Med Chem Lett. 2019 Oct 11;10(11):1518-1523. doi: 10.1021/acsmedchemlett.9b00141.
Curt D Haffner 1 Adam K Charnley 1 Christopher J Aquino 1 2 Linda Casillas 1 Máire A Convery 2 Julie A Cox 1 Mark A Elban 1 Nicole C Goodwin 1 Peter J Gough 1 Pamela A Haile 1 Terry V Hughes 1 2 Beth Knapp-Reed 1 Constantine Kreatsoulas 1 Ami S Lakdawala 1 Huijie Li 1 Yiqian Lian 1 David Lipshutz 1 John F Mehlmann 1 Michael Ouellette 1 Joseph Romano 1 Lisa Shewchuk 1 Arthur Shu 1 Bartholomew J Votta 1 Huiqiang Zhou 1 John Bertin 1 Robert W Marquis 1
Affiliations

Affiliations

  • 1 GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  • 2 GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
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.

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