Discovery of 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one derivatives as novel JAK inhibitors
| Autor: | Hiroaki Yamagishi, Shohei Shirakami, Akira Tanaka, Masamichi Inami, Takayuki Inoue, Ayako Moritomo, Yutaka Nakajima, Keiko Hatanaka, Fumie Takahashi, Hisao Hamaguchi, Yasuyuki Higashi |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Pyridines Pyridones Clinical Biochemistry Organ transplant rejection Pharmaceutical Science Pharmacology Crystallography X-Ray Biochemistry Structure-Activity Relationship Drug Discovery medicine Animals Cytochrome P-450 CYP3A Humans Pyrroles Protein Kinase Inhibitors Molecular Biology IC50 Cells Cultured Cell Proliferation Janus kinase inhibitor chemistry.chemical_classification Binding Sites Organic Chemistry Janus Kinase 3 Janus Kinase 1 Janus Kinase 2 Metabolic stability medicine.disease Protein Structure Tertiary Rats Molecular Docking Simulation chemistry Rats Inbred Lew Rheumatoid arthritis Microsomes Liver Molecular Medicine Signal transduction Janus kinase Spleen Tricyclic |
| Zdroj: | Bioorganic & Medicinal Chemistry. 23:4846-4859 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2015.05.028 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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