Design, synthesis, and evaluation of novel 3-amino-4-hydrazine-cyclobut-3-ene-1,2-diones as potent and selective CXCR2 chemokine receptor antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 19, 2009, Pages 5741-5745

  Liu, Shilan ^a   Liu, Yinhui ^a   Wang, Hongmei ^a   Ding, YiLi ^a   Wu, Hao ^a   Dong, Jingchao ^a   Wong, Angela ^a   Chen, Shu Hui ^a   Li, Ge ^a   Chan, Manuel ^b   Sawyer, Nicole ^b   Gervais, Francois G ^b   Henault, Martin ^b   Kargman, Stacia ^b   Bedard, Leanne L ^b   Han, Yongxin ^b   Friesen, Rick ^b   Lobell, Robert B ^c   Stout, David M ^c  

^a WUXI APPTEC   (China)

^b MERCK FROSST CENTRE FOR THERAPEUTIC RESEARCH   (Canada)

^c MERCK RESEARCH LABORATORIES   (United States)

Author keywords

3,4 Dioxocyclobut 1 enyl hydrazine; Antagonists; Chemokine receptor; CXCR2

Indexed keywords

3 AMINO 4 HYDRAZINE CYCLOBUT 3 ENE 1,2 DIONE DERIVATIVE; CHEMOKINE RECEPTOR ANTAGONIST; CHEMOKINE RECEPTOR CXCR1; CHEMOKINE RECEPTOR CXCR2; INTERLEUKIN 8; SCH 527123; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; CHEMOTAXIS; CONTROLLED STUDY; DRUG DESIGN; DRUG METABOLISM; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SCREENING; DRUG SELECTIVITY; DRUG STABILITY; DRUG SYNTHESIS; HUMAN; HUMAN CELL; MICROSOME; NONHUMAN; PROTEIN EXPRESSION; RECEPTOR AFFINITY; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTI-INFLAMMATORY AGENTS; CHEMOTAXIS; CHO CELLS; CRICETINAE; CRICETULUS; DRUG DESIGN; HUMANS; HYDRAZINES; INTERLEUKIN-8; MICROSOMES, LIVER; RATS; RECEPTORS, INTERLEUKIN-8B; STRUCTURE-ACTIVITY RELATIONSHIP;

RATTUS;

EID: 69949177611     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.08.014     Document Type: Article

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24. 2 and KOH were from SCRC (Shanghai, China). DMSO was from Sigma-Aldrich (Steinheim, Germany).Method: for each 200 μL reaction, a working mixture of receptor over-expressing membranes (0.020 μg/μL CXCR2 or 0.040 μg/μL CXCR1) and 2 mg/mL wheatgerm-agglutinin coated SPA beads was prepared in assay buffer. The assay buffer was 25 mM HEPES, 3 mM MgCl2, pH 7.4. This mixture was incubated on ice for 5 min. A 0.040 nM 125I labeled IL-8 stock solution was prepared in the assay buffer. Test compounds were serially diluted by half-log concentration in DMSO. The above solutions were added to a 96 well plate (Perking Elmer) in the following sequence: 45 μL assay buffer and 5 μL test compound or DMSO, 100 μL of membranes and SPA bead mixture and 50 μL [125I]IL-8 solution stock solution. The assay plates were incubated for 2 h at room temperature, keeping from light. Binding was detected using a Perking Elmer-Wallace Microbeta 1450 liquid scintillation counter. The data was analyzed using SigmaPlot (Systat Software Inc., San Jose, CA).