Novel dihydrothieno[2,3-e]indazole derivatives as IκB kinase inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 6, 2011, Pages 1758-1762

  Takahashi, Hiroyasu ^a   Shinoyama, Mariko ^a   Komine, Takashi ^a   Nagao, Muneki ^a   Suzuki, Masashi ^a   Tsuchida, Hisatoshi ^a   Katsuyama, Koichi ^a  

^a KYORIN PHARMACEUTICAL CO LTD   (Japan)

Author keywords

Dihydrothieno 2,3 e indazole; IKK inhibitor; IKK ; NF B

Indexed keywords

DIHYDROTHIENO[2,3 E]INDAZOLE DERIVATIVE; I KAPPA B KINASE INHIBITOR; INDAZOLE DERIVATIVE; LIPOPOLYSACCHARIDE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; CYTOKINE PRODUCTION; DOSE RESPONSE; DRUG EFFICACY; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN; HUMAN CELL; IC 50; IN VITRO STUDY; IN VIVO STUDY; INFLAMMATION; MONOCYTE; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION;

ANIMALS; I-KAPPA B KINASE; INDAZOLES; MICE; PROTEIN KINASE INHIBITORS;

EID: 79952360582     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.01.069     Document Type: Article

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16. 2 and incubated for 60 min at 25 °C. After the incubation, the plate was washed three times with PBS-0.05% Tween 20. Mouse monoclonal antibody for phospho IkB-α (1:7000, Cell signaling, 100 μL/well) was then added to the plate and incubated for 16 h at 4 °C. After the incubation, the plate was washed three times with PBS-0.05% Tween 20. HRP-conjugated rabbit polyclonal antibody for mouse IgG (1:7000, GE Healthcare, 100 μL/well) was added to the plate and incubated for 60 min at 25 °C. After the plate was washed, the amount of phosphorylation of IkB-α substrate was measured using TMB reagent (100 μL/well). Measurement of TNF-α inhibitory activity: Human monocyte THP-1 cells (2 × 105 cells/well) was incubated with serum-free RPMI-1640 containing the test compounds and LPS (0.2 μg/well) for 6 hr at 37 °C. TNF-α concentrations in the conditioned media were measured by ELISA methods.
17. Female DBA/2 mice were administered 2r by peroral gavage. After 60 min, LPS (1 μg/body) dissolved in 0.2 mL of saline was injected intraperitoneally. After 90 min, plasma TNF-α levels were analyzed with a commercial TNF-α ELISA kit.