Novel Tricyclic Inhibitors of IκB 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: WASHINGTON American Chemical Society 09.04.2009; Amer Chemical Soc
• Subjects: Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Chemistry, Medicinal; Life Sciences & Biomedicine; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; CELLS; POTENT; COLLAGEN; INFLAMMATORY RESPONSES; TRANSCRIPTION; GENE-EXPRESSION; ALPHA; PROLIFERATION; MICE; ARTHRITIS; Intravenous administration; Rat; Enzyme; Transferases; Rodentia; Cytokine; Oral administration; Tricyclic compound; In vitro; In vivo; Signal transduction; Vertebrata; Mammalia; Structure activity relation; Mouse; Animal; Inhibitor; Pharmacokinetics; Chemical synthesis; Tumor necrosis factor α
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm8015816

The design and synthesis of a novel series of oxazole-, thiazole-, and imidazole-based inhibitors of IκB 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.