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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.

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.
AuthorsHiroaki Yamagishi, Shohei Shirakami, Yutaka Nakajima, Akira Tanaka, Fumie Takahashi, Hisao Hamaguchi, Keiko Hatanaka, Ayako Moritomo, Masamichi Inami, Yasuyuki Higashi, Takayuki Inoue
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 23 Issue 15 Pg. 4846-4859 (Aug 01 2015) ISSN: 1464-3391 [Electronic] England
PMID26059596 (Publication Type: Journal Article)
CopyrightCopyright © 2015 Elsevier Ltd. All rights reserved.
Chemical References
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyridones
  • Pyrroles
  • Cytochrome P-450 CYP3A
  • Janus Kinase 1
  • Janus Kinase 2
  • Janus Kinase 3
  • pyrrolo(2, 3-b)pyridine
Topics
  • Animals
  • Binding Sites
  • Cell Proliferation (drug effects)
  • Cells, Cultured
  • Crystallography, X-Ray
  • Cytochrome P-450 CYP3A (metabolism)
  • Humans
  • Janus Kinase 1 (antagonists & inhibitors, metabolism)
  • Janus Kinase 2 (antagonists & inhibitors, metabolism)
  • Janus Kinase 3 (antagonists & inhibitors, metabolism)
  • Male
  • Microsomes, Liver (metabolism)
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Protein Structure, Tertiary
  • Pyridines (chemistry)
  • Pyridones (chemical synthesis, chemistry, pharmacology)
  • Pyrroles (chemistry)
  • Rats
  • Rats, Inbred Lew
  • Spleen (cytology, drug effects, metabolism)
  • Structure-Activity Relationship

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