Design and optimization of imidazole derivatives as potent CXCR3 antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 2, 2008, Pages 608-613

  Du, Xiaohui ^a   Chen, Xiaoqi ^a   Mihalic, Jeffrey T ^a   Deignan, Jeffrey ^a   Duquette, Jason ^a   Li, An Rong ^a   Lemon, Bryan ^a   Ma, Ji ^a   Miao, Shichang ^a   Ebsworth, Karen ^a   Sullivan, Timothy J ^a   Tonn, George ^a   Collins, Tassie L ^a   Medina, Julio C ^a  

^a AMGEN INC   (United States)

Author keywords

Chemokine; CXCL10; CXCL11; CXCL9; CXCR3; Imidazole; IP10; ITAC; Mig

Indexed keywords

CHEMOKINE RECEPTOR ANTAGONIST; CHEMOKINE RECEPTOR CXCR3; GLUTATHIONE; IMIDAZOLE DERIVATIVE;

ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; DRUG ABSORPTION; DRUG DESIGN; DRUG POTENCY; DRUG SCREENING; DRUG SYNTHESIS; IC 50; MEAN RESIDENCE TIME; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; DRUG DESIGN; HUMANS; IMIDAZOLES; MICE; MICE, KNOCKOUT; RATS; RECEPTORS, CXCR3; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 38149099256     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.11.072     Document Type: Article

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29. 1H NMR and LC/MS and their purity was determined to be >95% by reverse phase HPLC.
30. 125I-IP10 binding assay in buffer with the exception that EDTA-anti-coagulated human plasma (from frozen stocks) was used instead of the RPMI buffer. ITAC in vitro cell migration assay: 100 ng/ml of ITAC was used in the presence of 100% human plasma. Compounds were measured by their ability to inhibit CXCR3 mediated cell migration in response to ITAC.
31. Chiral purity was analyzed with ChiralTech AD column with hexanes and isopropanol as solvents. The enantiomeric purity was higher than 95% ee with this synthetic route.