Novel tricyclic inhibitors of IKK2: Discovery and SAR leading to the identification of 2-methoxy- N-((6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3- b]pyridin-7-yl)pyridin-2-yl)methyl)acetamide (BMS-066)

• Published in: Bioorganic & medicinal chemistry letters 2011-12, Vol.21 (23), p.7006-7012
• Main Authors: Watterson, Scott H., Langevine, Charles M., Van Kirk, Katy, Kempson, James, Guo, Junquing, Spergel, Steven H., Das, Jagabandhu, Moquin, Robert V., Dyckman, Alaric J., Nirschl, David, Gregor, Kurt, Pattoli, Mark A., Yang, XiaoXia, McIntyre, Kim W., Yang, Guchen, Galella, Michael A., Booth-Lute, Hollie, Chen, Laishun, Yang, Zheng, Wang-Iverson, David, McKinnon, Murray, Dodd, John H., Barrish, Joel C., Burke, James R., Pitts, William J.
• Format: Article
• Language: English
• Subjects: Acetamides - chemical synthesis; Acetamides - chemistry; Acetamides - pharmacology; Administration, Oral; animal models; Animals; BMS-066; Drug Discovery; Enzyme Activation - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Heterocyclic Compounds, 3-Ring - chemical synthesis; Heterocyclic Compounds, 3-Ring - chemistry; Heterocyclic Compounds, 3-Ring - pharmacology; Humans; I-kappa B Kinase - antagonists & inhibitors; IKK; IKK2; IKKβ; inflammatory bowel disease; Inflammatory Bowel Diseases - drug therapy; Inhibitory Concentration 50; Mice; Molecular Structure; NF-κB; pharmacokinetics; physicochemical properties; Rats; Structure-Activity Relationship; structure-activity relationships
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.09.111

The synthesis, structure–activity relationships (SAR), and biological results of pyridyl-substituted azaindole based tricyclic inhibitors of IKK2 are described. Compound 4m demonstrated potent in vitro potency, acceptable pharmacokinetic and physicochemical properties, and efficacy when dosed orally in a mouse model of inflammatory bowel disease.