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
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.07.043

[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 inhibitor; however, it had poor oral absorption due to low membrane permeability. Here, we report the structural modification of compound 2 into the tricyclic dipyrrolopyridine 18a focusing on reduction of polar surface area (PSA), which exhibits potent in vitro activity, improved membrane permeability and good oral bioavailability. Compound 18a showed efficacy in rat heterotopic cardiac transplants model.