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

  • Bioorg Med Chem. 2015 Aug 1;23(15):4846-4859. doi: 10.1016/j.bmc.2015.05.028.
Hiroaki Yamagishi  1 ,  Shohei Shirakami  2 ,  Yutaka Nakajima  2 ,  Akira Tanaka  2 ,  Fumie Takahashi  2 ,  Hisao Hamaguchi  2 ,  Keiko Hatanaka  2 ,  Ayako Moritomo  2 ,  Masamichi Inami  2 ,  Yasuyuki Higashi  2 ,  Takayuki Inoue  3
Affiliations
  • 1. Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: [email protected].
  • 2. Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
  • 3. Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: [email protected].
PMID: 26059596 DOI: 10.1016/j.bmc.2015.05.028
Abstract

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.

Keywords
Autoimmune diseases; IL-2; Immunomodulator; Janus kinase inhibitor; Organ transplant rejection.