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
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DOI：
10.1021/acsmedchemlett.9b00141
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发表时间：
2019-11-01
影响因子：
4.2
通讯作者：
Marquis, Robert W.
中科院分区：
文献类型：
--
作者：
Haffner, Curt D.;Charnley, Adam K.;Marquis, Robert W.
在此，我们报告发现吡唑甲酰胺类化合物作为受体相互作用蛋白2激酶（RIP2）的新型、强效和激酶选择性抑制剂。基于片段的筛选和设计原则导致了抑制剂系列的鉴定，X射线晶体学用于告知关键结构变化。通过吡唑环上N1和C5 N位置的关键取代，实现了显着的激酶选择性和效力。桥连双环吡唑并甲酰胺11代表RIP2的选择性和有效的抑制剂，并将允许更详细地研究RIP2抑制作为自身炎性疾病的治疗靶点。
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.