Synthesis and biological evaluation of tricyclic anilinopyrimidines as IKKβ inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 12; pp. 3821 - 3825
• Main Authors: Crombie, Aimee L., Sum, Fuk-Wah, Powell, Dennis W., Hopper, Darrin W., Torres, Nancy, Berger, Dan M., Zhang, Yixian, Gavriil, Maria, Sadler, Tammy M., Arndt, Kim
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.06.2010; Elsevier
• Subjects: Antineoplastic agents; Biological and medical sciences; General aspects; IKK inhibitor; IKK-2; IKKβ; Immunomodulators; Medical sciences; NF-κB; Pharmacology. Drug treatments; NF-κB; IKK-2; IKKβ; IKK inhibitor; Sulfonamide; Enzyme; Transferases; Non-specific serine/threonine protein kinase; Enzyme inhibitor; Aniline derivatives; Tricyclic compound; Biological activity; IκB kinase; Signal transduction; Cell line; Colon; Transcription factor NFκB; Chemical synthesis; Tumor cell; Aromatic amine
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.04.022

A series of anilinopyrimidines and their tricyclic analogues were synthesized and evaluated as IKKβ inhibitors. A series of tricyclic anilinopyrimidines were synthesized and evaluated as IKKβ inhibitors. Several analogues, including tricyclic phenyl (10, 18a, 18c, 18d, and 18j) and thienyl (26 and 28) derivatives were shown to have good in vitro enzyme potency and excellent cellular activity. Pharmaceutical profiling of a select group of tricyclic compounds compared to the non-tricyclic analogues suggested that in some cases, the improved cellular activity may be due to increased clogP and permeability.