Discovery of 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one derivatives as novel JAK inhibitors

被引：16
|
作者：
Yamagishi, Hiroaki [1 ]
Shirakami, Shohei [1 ]
Nakajima, Yutaka [1 ]
Tanaka, Akira [1 ]
Takahashi, Fumie [1 ]
Hamaguchi, Hisao [1 ]
Hatanaka, Keiko [1 ]
Moritomo, Ayako [1 ]
Inami, Masamichi [1 ]
Higashi, Yasuyuki [1 ]
Inoue, Takayuki [1 ]
机构：
[1] Astellas Pharma Inc, Drug Discovery Res, Tsukuba, Ibaraki 3058585, Japan
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 15期
关键词：
Janus kinase inhibitor; IL-2; Organ transplant rejection; Autoimmune diseases; Immunomodulator; LIGAND-BINDING; POTENT; IMIDAZOPYRROLOPYRIDINES; IDENTIFICATION; SELECTIVITY; REJECTION; DISEASES; PATHWAY; PATENTS; DESIGN;
D O I：
10.1016/j.bmc.2015.05.028
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Because Janus kinases (JAKs) play a crucial role in cytokine-mediated signal transduction, JAKs are an attractive target for the treatment of organ transplant rejection and autoimmune diseases such as rheumatoid arthritis (RA). To identify JAK inhibitors, we focused on the 1H-pyrrolo[2,3-b]pyridine derivative 3, which exhibited moderate JAK3 and JAK1 inhibitory activities. Optimization of 3 identified the tricyclic imidazo-pyrrolopyridinone derivative 19, which exhibited potent JAK3 and JAK1 inhibitory activities (IC50 = 1.1 nM, 1.5 nM, respectively) with favorable metabolic stability. (C) 2015 Elsevier Ltd. All rights reserved.
引用
收藏
页码：4846 / 4859
页数：14
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