3,6-二氢咪唑并[4,5-d]吡咯并[2,3-b]吡啶-2(1H)-酮衍生物作为新型JAK抑制剂的发现
Discovery of 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one derivatives as novel JAK inhibitors.
作者信息
Yamagishi Hiroaki, Shirakami Shohei, Nakajima Yutaka, Tanaka Akira, Takahashi Fumie, Hamaguchi Hisao, Hatanaka Keiko, Moritomo Ayako, Inami Masamichi, Higashi Yasuyuki, Inoue Takayuki
机构信息
Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
出版信息
Bioorg Med Chem. 2015 Aug 1;23(15):4846-4859. doi: 10.1016/j.bmc.2015.05.028. Epub 2015 May 23.
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.
由于Janus激酶（JAKs）在细胞因子介导的信号转导中起关键作用，因此JAKs是治疗器官移植排斥反应和自身免疫性疾病（如类风湿性关节炎（RA））的一个有吸引力的靶点。为了鉴定JAK抑制剂，我们聚焦于1H-吡咯并[2,3-b]吡啶衍生物3，其表现出中等程度的JAK3和JAK1抑制活性。对3进行优化后得到三环咪唑-吡咯并吡啶酮衍生物19，其表现出强效的JAK3和JAK1抑制活性（IC50分别为1.1 nM、1.5 nM），且具有良好的代谢稳定性。
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