title: Novel tricyclic inhibitors of IkappaB kinase.
abstract: 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.
authors.affiliation: Departments of Discovery Chemistry, Discovery Biology, and Metabolism and Pharmacokinetics and Synthesis and Analysis Technology Team, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543-4000, USA.
authors.forename: James
authors.initials: J
authors.lastname: Kempson
authors.forename: Steven H
authors.initials: SH
authors.lastname: Spergel
authors.forename: Junqing
authors.initials: J
authors.lastname: Guo
authors.forename: Claude
authors.initials: C
authors.lastname: Quesnelle
authors.forename: Patrice
authors.initials: P
authors.lastname: Gill
authors.forename: Dominique
authors.initials: D
authors.lastname: Belanger
authors.forename: Alaric J
authors.initials: AJ
authors.lastname: Dyckman
authors.forename: Tianle
authors.initials: T
authors.lastname: Li
authors.forename: Scott H
authors.initials: SH
authors.lastname: Watterson
authors.forename: Charles M
authors.initials: CM
authors.lastname: Langevine
authors.forename: Jagabandhu
authors.initials: J
authors.lastname: Das
authors.forename: Robert V
authors.initials: RV
authors.lastname: Moquin
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Furch
authors.forename: Anne
authors.initials: A
authors.lastname: Marinier
authors.forename: Marco
authors.initials: M
authors.lastname: Dodier
authors.forename: Alain
authors.initials: A
authors.lastname: Martel
authors.forename: David
authors.initials: D
authors.lastname: Nirschl
authors.forename: Katy
authors.initials: K
authors.lastname: Van Kirk
authors.forename: James R
authors.initials: JR
authors.lastname: Burke
authors.forename: Mark A
authors.initials: MA
authors.lastname: Pattoli
authors.forename: Kathleen
authors.initials: K
authors.lastname: Gillooly
authors.forename: Kim W
authors.initials: KW
authors.lastname: McIntyre
authors.forename: Laishun
authors.initials: L
authors.lastname: Chen
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Punit H
authors.initials: PH
authors.lastname: Marathe
authors.forename: David
authors.initials: D
authors.lastname: Wang-Iverson
authors.forename: John H
authors.initials: JH
authors.lastname: Dodd
authors.forename: Murray
authors.initials: M
authors.lastname: McKinnon
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.forename: William J
authors.initials: WJ
authors.lastname: Pitts
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D010080:Oxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D007093:Imidazoles; D008070:Lipopolysaccharides; D010080:Oxazoles; D011993:Recombinant Fusion Proteins; C439524:TNF protein, human; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D005982:Glutathione Transferase; D051550:I-kappa B Kinase