2-Benzimidazolyl-9-(chroman-4-yl)-purinone derivatives as JAK3 inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 23; pp. 6788 - 6792
• Main Authors: Cole, Andrew G., Bohnstedt, Adolph C., Paradkar, Vidyadhar, Kingsbury, Celia, Quintero, Jorge G., Park, Haengsoon, Lu, Yingchun, You, Ming, Neagu, Irina, Diller, David J., Letourneau, Jeffrey J., Shao, Yuefei, James, Ray A., Riviello, Christopher M., Ho, Koc-Kan, Lin, Tsung H., Wang, Bojing, Appell, Kenneth C., Sills, Matthew, Quadros, Elizabeth, Kimble, Earl F., Ohlmeyer, Michael H.J., Webb, Maria L.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.12.2009; Elsevier
• Subjects: Animals; Benzimidazole; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Biological and medical sciences; Chroman; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Immunomodulators; Interferon-gamma - biosynthesis; Interleukin-2 - antagonists & inhibitors; JAK3; Janus kinase; Janus Kinase 3 - antagonists & inhibitors; Medical sciences; Mice; Models, Animal; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Purines - chemical synthesis; Purines - chemistry; Purines - pharmacology; Purinone; Rheumatoid arthritis; Stereoisomerism; Structure-Activity Relationship; Janus kinase; Chroman; JAK3; Rheumatoid arthritis; Benzimidazole; Purinone; Purine derivatives; Intravenous administration; Diseases of the osteoarticular system; Autoimmune disease; Inflammatory joint disease; Chroman derivatives; Chemical synthesis; Immunopathology; Enzyme; Transferases; Rodentia; Oral administration; Non-specific protein-tyrosine kinase; Biological activity; Vertebrata; Chronic; Mammalia; Mouse; Purinone derivatives; Benzimidazole derivatives; Animal; Inhibitor; Fluorine Organic compounds; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.09.080

A novel class of 2-benzimidazoylpurinone-based JAK3 inhibitors with excellent kinase activity is described. Compound 24 demonstrates good oral bioavailability and in vivo efficacy in an acute mechanistic mouse model. A novel class of Janus tyrosine kinase 3 (JAK3) inhibitors based on a 2-benzimidazoylpurinone core structure is described. Through substitution of the benzimidazoyl moiety and optimization of the N-9 substituent of the purinone, compound 24 was identified incorporating a chroman-based functional group. Compound 24 shows excellent kinase activity, good oral bioavailability and demonstrates efficacy in an acute mechanistic mouse model through inhibition of interleukin-2 (IL-2) induced interferon-γ (INF-γ) production.