Discovery of tricyclic dipyrrolopyridine derivatives as novel JAK inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 25; no. 20; pp. 5311 - 5326
• Main Authors: Yamagishi, Hiroaki, Inoue, Takayuki, Nakajima, Yutaka, Maeda, Jun, Tominaga, Hiroaki, Usuda, Hiroyuki, Hondo, Takeshi, Moritomo, Ayako, Nakamori, Fumihiro, Ito, Misato, Nakamura, Koji, Morio, Hiroki, Higashi, Yasuyuki, Inami, Masamichi, Shirakami, Shohei
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.10.2017; Elsevier
• Subjects: Adjuvants, Immunologic - administration & dosage; Adjuvants, Immunologic - chemistry; Adjuvants, Immunologic - pharmacology; Administration, Oral; Animals; Autoimmune diseases; Biochemistry & Molecular Biology; Biological Availability; Cell Membrane Permeability - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Female; Graft Survival - drug effects; Heart Transplantation; Humans; IL-2; Immunomodulator; Janus kinase inhibitor; Janus Kinases - antagonists & inhibitors; Janus Kinases - metabolism; Life Sciences & Biomedicine; Male; Molecular Structure; Organ transplant rejection; Pharmacology & Pharmacy; Physical Sciences; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyridines - administration & dosage; Pyridines - chemistry; Pyridines - pharmacology; Pyrroles - administration & dosage; Pyrroles - chemistry; Pyrroles - pharmacology; Rats; Rats, Inbred ACI; Rats, Inbred Lew; Rats, Sprague-Dawley; Science & Technology; Structure-Activity Relationship; Immunomodulator; Organ transplant rejection; IL-2; Autoimmune diseases; Janus kinase inhibitor; POTENT; DISEASES; PATHWAY; REJECTION; PATENTS

[Display omitted] Janus kinases (JAKs) play a crucial role in cytokine mediated signal transduction. JAK inhibitors have emerged as effective immunomodulative agents for the prevention of transplant rejection. We previously reported that the tricyclic imidazo-pyrrolopyridinone 2 is a potent JAK inhi...