Synthesis, initial SAR and biological evaluation of 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine derived inhibitors of IκB kinase

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 10, 2009, Pages 2646-2649

  Kempson, James ^a   Guo, Junqing ^a   Das, Jagabandhu ^a   Moquin, Robert V ^a   Spergel, Steven H ^a   Watterson, Scott H ^a   Langevine, Charles M ^a   Dyckman, Alaric J ^a   Pattoli, Mark ^a   Burke, James R ^a   Yang, XiaoXia ^a   Gillooly, Kathleen M ^a   McIntyre, Kim W ^a   Chen, Laishun ^a   Dodd, John H ^a   McKinnon, Murray ^a   Barrish, Joel C ^a   Pitts, William J ^a  

^a BRISTOL MYERS SQUIBB RESEARCH AND DEVELOPMENT   (United States)

Author keywords

IKK; LPS; SAR; TNF

Indexed keywords

1,6 DIHYDROIMIDAZO[4,5 D]PYRROLO[2,3 B]PYRIDIN 4 AMINE DERIVATIVE; I KAPPA B KINASE; I KAPPA B KINASE INHIBITOR; PYRIDINE DERIVATIVE; TUMOR NECROSIS FACTOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG HALF LIFE; DRUG STRUCTURE; DRUG SYNTHESIS; IC 50; INFLAMMATION; NONHUMAN; RAT; REACTION ANALYSIS; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS;

ANIMALS; I-KAPPA B KINASE; IMIDAZOLES; LIPOPOLYSACCHARIDES; PROTEIN KINASE INHIBITORS; PYRIMIDINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; TUMOR NECROSIS FACTOR-ALPHA;

RATTUS;

EID: 65349119487     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.03.159     Document Type: Article

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23. 2) as measured using fluorescence polarization.
24. 2. The cell supernatants were removed and assayed for TNF-α by ELISA (R&D Systems).
25. LPS-induced Serum TNF-α in Rats: Male Lewis rats (175-200 g, Harlan) were dosed by oral gavage with vehicle (50% PEG400, 50% 0.02 N HCl) or 4k in vehicle. Four hours later, rats were injected intraperitoneally with 1 mL per rat of 100 μg lipopolysaccharide (LPS, Escherichia coli strain 0111:B4, Sigma-Aldrich, St. Louis, MO) suspended in phosphate buffered saline. Ninety minutes after LPS challenge, blood was collected from the retro-orbital sinus under isoflurane anesthesia. Serum was separated from clotted samples by centrifugation (5 min, 5000g×, room temperature) and analyzed for the levels of TNF-α by ELISA according to the manufacturer's instructions (BioSource, Camarillo, CA). Results are shown as mean ± SD of n = 8 rats per treatment group. Unless otherwise noted, statistical significance was determined using a one-way analysis of variance (ANOVA) with a Dunnett's post-test. Values of p < 0.05 were considered significant.
26. For rat whole blood experiments, blood was collected by cardiac puncture in collection tubes containing ACD-a as an anticoagulant. 300 μL of pooled whole blood was pipetted into deep-well 96 well assay plates (Costar), and inhibitor in phosphate buffered saline containing 16% (v/v) DMSO was then added to give a final DMSO concentration of 0.2% (v/v). After incubating 45 min at 37 °C, lipopolysaccahride (LPS, S.Typhosa, Sigma) was added to a final concentration of 5 μg /mL. After a 4 h incubation at 37 °C, the plates were centrifuged for 10 min at 14,000 rpm and plasma removed for TNFα measurement by ELISA (Biosource).