Haffner Curt D, Charnley Adam K, Aquino Christopher J, Casillas Linda, Convery Máire A, Cox Julie A, Elban Mark A, Goodwin Nicole C, Gough Peter J, Haile Pamela A, Hughes Terry V, Knapp-Reed Beth, Kreatsoulas Constantine, Lakdawala Ami S, Li Huijie, Lian Yiqian, Lipshutz David, Mehlmann John F, Ouellette Michael, Romano Joseph, Shewchuk Lisa, Shu Arthur, Votta Bartholomew J, Zhou Huiqiang, Bertin John, Marquis Robert W
GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
ACS Med Chem Lett. 2019 Oct 11;10(11):1518-1523. doi: 10.1021/acsmedchemlett.9b00141. eCollection 2019 Nov 14.
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 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.
在此,我们报告了吡唑并甲酰胺作为受体相互作用蛋白2激酶(RIP2)新型、强效且具有激酶选择性的抑制剂的发现。基于片段的筛选和设计原则导致了该抑制剂系列的鉴定,并利用X射线晶体学来指导关键的结构变化。通过对吡唑环上N1和C5氮原子位置进行关键取代,实现了显著的激酶选择性和效力。桥连双环吡唑并甲酰胺是RIP2的一种选择性强效抑制剂,将有助于更详细地研究RIP2抑制作为自身炎症性疾病治疗靶点的情况。