Discovery of potent, selective, and orally bioavailable inhibitors of interleukin-1 receptor-associate kinase-4. Issue 23 (1st December 2015)

• Record Type: Journal Article
• Authors: Wang, Zhulun; Sun, Daqing; Johnstone, Sheree; Cao, Zhaodan; Gao, Xiong; Jaen, Juan C.; Liu, Jingqian; Lively, Sarah; Miao, Shichang; Sudom, Athena; Tomooka, Craig; Walker, Nigel P.C.; Wright, Matthew; Yan, Xuelei; Ye, Qiuping; Powers, Jay P.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 23(2015)
• Page Start: 5546
• Page End: 5550
• Publication Date: 2015-12-01
• Subjects: MeCN acetonitrile -- CL clearance -- Dess–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′, N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate -- HOBT hydroxybenzotriazole -- NMM N-methylmorpholine -- THF tetrahydrofuran; Interleukin-1 receptor-associate kinase-4 -- N-Acyl-2-aminobenzimidazole -- Inflammation; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.10.060
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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 of16, a highly potent, selective, and orally bioavailable inhibitor of IRAK-4.