Novel tricyclic inhibitors of IkappaB kinase

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...

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Veröffentlicht in:	Journal of medicinal chemistry 2009-04, Vol.52 (7), p.1994-2005
Hauptverfasser:	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:	Artikel
Sprache:	eng
Schlagworte:	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
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Beschreibung
Zusammenfassung:	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.
ISSN:	1520-4804
DOI:	10.1021/jm8015816