Novel tricyclic inhibitors of IkappaB kinase

• Published in: Journal of medicinal chemistry Vol. 52; no. 7; pp. 1994 - 2005
• Main Authors: Kempson, James, Spergel, Steven H, Guo, Junqing, Quesnelle, Claude, Gill, Patrice, Belanger, Dominique, Dyckman, Alaric J, Li, Tianle, Watterson, Scott H, Langevine, Charles M, Das, Jagabandhu, Moquin, Robert V, Furch, Joseph A, Marinier, Anne, Dodier, Marco, Martel, Alain, Nirschl, David, Van Kirk, Katy, Burke, James R, Pattoli, Mark A, Gillooly, Kathleen, McIntyre, Kim W, Chen, Laishun, Yang, Zheng, Marathe, Punit H, Wang-Iverson, David, Dodd, John H, McKinnon, Murray, Barrish, Joel C, Pitts, William J
• Format: Journal Article
• Language: English
• Published: United States 09.04.2009
• Subjects: Animals; Crystallography, X-Ray; Female; Glutathione Transferase - genetics; Glutathione Transferase - metabolism; Heterocyclic Compounds, 3-Ring - chemical synthesis; Heterocyclic Compounds, 3-Ring - pharmacokinetics; Heterocyclic Compounds, 3-Ring - pharmacology; Humans; I-kappa B Kinase - antagonists & inhibitors; I-kappa B Kinase - genetics; Imidazoles - chemical synthesis; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; In Vitro Techniques; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Lipopolysaccharides - pharmacology; Mice; Mice, Inbred BALB C; Microsomes, Liver - metabolism; Oxazoles - chemical synthesis; Oxazoles - pharmacokinetics; Oxazoles - pharmacology; Rats; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - pharmacokinetics; Thiazoles - pharmacology; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 1520-4804
• DOI: 10.1021/jm8015816

The design and synthesis of a novel series of oxazole-, thiazole-, and imidazole-based inhibitors of IkappaB kinase (IKK) are reported. Biological activity was improved compared to the pyrazolopurine lead, and the expedient synthesis of the new tricyclic systems allowed for efficient exploration of structure-activity relationships. This, combined with an iterative rat cassette dosing strategy, was used to identify compounds with improved pharmacokinetic (PK) profiles to advance for in vivo evaluation.