Synthesis and biological evaluation of 4-amino derivatives of benzimidazoquinoxaline, benzimidazoquinoline, and benzopyrazoloquinazoline as potent IKK inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 5, 2007, Pages 1233-1237

  Beaulieu, Francis ^a   Ouellet, Carl ^a   Ruediger, Edward H ^a   Belema, Makonen ^b   Qiu, Yuping ^b   Yang, Xuejie ^b   Banville, Jacques ^a   Burke, James R ^b   Gregor, Kurt R ^b   MacMaster, John F ^b   Martel, Alain ^a   McIntyre, Kim W ^b   Pattoli, Mark A ^b   Zusi, F Christopher ^b   Vyas, Dolatrai ^b  

^a BRISTOL MYERS SQUIBB   (United States)

^b Department of Discovery Chemistry ^*  (United States)

Author keywords

IKK inhibitors; NF B; Quinoxaline; TNF

Indexed keywords

BENZIMIDAZOQUINOLINE; BENZIMIDAZOQUINOXALINE; BENZOPYRAZOLOQUINAZOLINE; BMS 345541; I KAPPA B KINASE INHIBITOR; QUINAZOLINE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; BIOLOGICAL ACTIVITY; DRUG POTENCY; DRUG SYNTHESIS; IC 50;

BENZIMIDAZOLES; CELL LINE; HETEROCYCLIC COMPOUNDS WITH 4 OR MORE RINGS; HUMANS; I-KAPPA B KINASE; INHIBITORY CONCENTRATION 50; QUINAZOLINES; QUINOLINES; QUINOXALINES; STRUCTURE-ACTIVITY RELATIONSHIP; SUBSTRATE SPECIFICITY;

EID: 33846968154     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.12.017     Document Type: Article

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28. 4: 262.1219; found 262.1226.
29. 3SnCl).
30. 2, 30 mM sodium phosphate, 3 mM NaCl, 0.6 mM potassium phosphate, 1 mM KCl, 1 mM dithiothreitol, 5% (w/v) glycerol, and 475 μg/mL bovine serum albumin.
31. 5 cells/well in 180 μL RPMI-1640/10% FBS) were treated with inhibitors for 1 h prior to stimulation with 100 ng/mL LPS. Measurements of the amount of TNF-α in the supernatants were made after 6 h of LPS stimulation. Specific enzyme immunoassay kits from Pharmingen (OptEIA) were used in quantitating each cytokine.
32. Compound 7b was screened against other kinases (IKK-ε, LCK, EMT) and failed to show inhibition at concentrations as high as 50 μM (data not shown). Enzyme kinetic analysis of inhibition was not performed to investigate the binding mechanism of these new inhibitors.
33. Based on inspection of the structures and physicochemical properties, the reason for the significant loss in cellular potency for 13a and 18b remains unclear.
34. LPS-induced serum TNF-α in mice. The general procedure of Ghezzi et al. (Cytokine 2000, 12, 1205-1210) was followed. Briefly, 0.2 mL of an aqueous solution of an inhibitor was administered by peroral gavage to 6- to 8-week-old female BALB/c mice (Harlan) 1 h prior to a challenge with an intraperitoneal dose of 1 μg Escherichia coli LPS (from strain O111:B4, Sigma) in 500 μL phosphate-buffered saline. Blood was collected from mice 90 min after LPS challenge and the levels of TNF-α in the serum measured by EIA (R&D systems). Inhibition by the inhibitor was calculated from control animals which received LPS challenge but no inhibitor (vehicle only). Mice receiving no LPS challenge gave no detectable serum TNF-α.