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Discovery of 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one derivatives as novel JAK inhibitors. 2015
Hiroaki Yamagishi, and
Shohei Shirakami, and
Yutaka Nakajima, and
Akira Tanaka, and
Fumie Takahashi, and
Hisao Hamaguchi, and
Keiko Hatanaka, and
Ayako Moritomo, and
Masamichi Inami, and
Yasuyuki Higashi, and
Takayuki Inoue
Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: hiroaki.yamagishi@astellas.com.
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.
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