Discovery of potent, selective, and orally bioavailable inhibitors of interleukin-1 receptor-associate kinase-4
详细信息 查看全文
- 作者：Zhulun Wang ; zwang@amgen.com" class="auth_mail" title="E-mail the corresponding author ; Daqing Sun ; daqingsun@yahoo.com" class="auth_mail" title="E-mail the corresponding author ; Sheree Johnstone ; Zhaodan Cao ; Xiong Gao ; Juan C. Jaen ; Jingqian Liu ; Sarah Lively ; Shichang Miao ; Athena Sudom ; Craig Tomooka ; Nigel P.C. Walker ; Matthew Wright ; Xuelei Yan ; Qiuping Ye ; Jay P. Powers
- 关键词：MeCN ; acetonitrile ; CL ; clearance ; Dess&ndash ; Martin periodinane ; 1 ; 1 ; 1-tris(acetyloxy)-1 ; 1-dihydro-1 ; 2-benziodoxol-3-(1H)-one ; DIBALH ; diisobutylaluminum hydride ; DMF ; N ; N-dimethylformamide ; EtOAc ; ethyl acetate ; HBTU ; N ; N ; N&prime ; N&prime ; -tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate ; HOBT ; hydroxybenzotriazole ; NMM ; N-methylmorpholine ; THF ; tetrahydrofuran
- 刊名：Bioorganic & Medicinal Chemistry Letters
- 出版年：2015
- 出版时间：1 December 2015
- 年：2015
- 卷：25
- 期：23
- 页码：5546-5550
- 全文大小：2785 K
文摘
In this Letter, we report the continued optimization of the N-acyl-2-aminobenzimidazole series, focusing in particular on the N-alkyl substituent and 5-position of the benzimidazole based on the binding mode and the early SAR. These efforts led to the discovery of 16, a highly potent, selective, and orally bioavailable inhibitor of IRAK-4.