Imidazo-pyrazine derivatives as potent CXCR3 antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 17, 2009, Pages 5200-5204

  Du, Xiaohui ^a   Gustin, Darin J ^a   Chen, Xiaoqi ^a   Duquette, Jason ^a   McGee, Lawrence R ^a   Wang, Zhulun ^a   Ebsworth, Karen ^a   Henne, Kirk ^a   Lemon, Bryan ^a   Ma, Ji ^a   Miao, Shichang ^a   Sabalan, Emmanuel ^a   Sullivan, Timothy J ^a   Tonn, George ^a   Collins, Tassie L ^a   Medina, Julio C ^a  

^a AMGEN INC   (United States)

Author keywords

CXCR3 antagonist; Imidazo pyrazine

Indexed keywords

AMG 487; ANTIINFLAMMATORY AGENT; CHEMOKINE RECEPTOR ANTAGONIST; CHEMOKINE RECEPTOR CXCR3; CHEMOKINE RECEPTOR CXCR3 ANTAGONIST; GAMMA INTERFERON INDUCIBLE PROTEIN 10; IMIDAZOPYRAZINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIINFLAMMATORY ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG SYNTHESIS; FEMALE; HUMAN; HUMAN CELL; IC 50; MEAN RESIDENCE TIME; MOUSE; NONHUMAN; PERIPHERAL BLOOD MONONUCLEAR CELL; REACTION ANALYSIS; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTI-INFLAMMATORY AGENTS; BENZENEACETAMIDES; CYCLIC S-OXIDES; HUMANS; IMIDAZOLES; MICE; MOLECULAR CONFORMATION; PYRAZINES; RATS; RECEPTORS, CXCR3;

EID: 68349152499     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.07.021     Document Type: Article

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29. See Ref. 13b for assay protocol.
30. 1H NMR and LC/MS and were >95% in purity by reverse phase HPLC. Chiral purity was analyzed with ChiralTech AD column. The enantiomeric purity was higher than 95% ee.
31. This assay measures cell-surface CXCR3 occupancy by FACS analysis of fluorescent using a fluorescently-tagged anti-CXCR3 antibody specific to CXCR3. Addition of the CXCR3 ligand, ITAC, results in the loss of fluorescent signal of antibody due to the competing ligand binding. The antagonist blocks ITAC binding against receptor, but does not compete against anti-CXCR3 antibody binding to CXCR3 receptor. The fluorescent signal of the antibody was restored with the addition of the antagonists. An ITAC concentration of 500 ng/ml was used in the assay.
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33. The 10 mg/ml group used 4.8 mg/kg/day of compound; 3 mg/ml used 1.44 mg/kg/day of compound; and 1 mg/ml used 0.48 mg/kg/day of compound. For more information of Alzet osmotic mini-pump, please visit http://www.alzet.com/downloads/TIM.pdf.