Discovery of small molecule benzimidazole antagonists of the chemokine receptor CXCR3

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 5, 2008, Pages 1573-1576

  Hayes, Martin E ^a   Wallace, Grier A ^a   Grongsaard, Pintipa ^a   Bischoff, Agnieszka ^a   George, Dawn M ^a   Miao, Wenyan ^a   McPherson, Michael J ^a   Stoffel, Robert H ^a   Green, David W ^a   Roth, Gregory P ^a  

^a ABBOTT LABORATORIES   (United States)

Author keywords

2 Iminobenzimidazole; Benzimidazole; Chemokine; Chemokine antagonist; CXCL10; CXCR3; IP 10; Multiple sclerosis; Partial solubility

Indexed keywords

ACETOPHENONE; BENZIMIDAZOLE DERIVATIVE; CHEMOKINE RECEPTOR ANTAGONIST; CHEMOKINE RECEPTOR CXCR3;

ARTICLE; CHEMICAL MODIFICATION; DRUG ACTIVITY; DRUG PROTEIN BINDING; DRUG SCREENING; HIGH THROUGHPUT SCREENING; PHYSICAL CHEMISTRY;

BENZIMIDAZOLES; MOLECULAR STRUCTURE; RECEPTORS, CXCR3; STRUCTURE-ACTIVITY RELATIONSHIP;

MURINAE;

EID: 39849110155     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.01.074     Document Type: Article

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25. 125I]-labeled CXCL10 was purchased from Perkin-Elmer and used at 50 pM per assay.
26. 16 coupling protein using a FLIPR instrument (Molecular Devices). All compounds were dissolved in DMSO and assays run at a final DMSO concentration of 1% (v/v). Human CXCL10 was purchased from Peprotech and used at a final assay concentration of 30 nM.
27. For example, equilibrium solubility as measured by CLND detection of a 100-mM aqueous solution of compound 1 is 4.5 μM as compared with 84 μM for compound 12d and 79 μM for compound 12o.
28. Female SJL mice were obtained from Jackson Labs and compound 12o was dosed in a vehicle of D5W with 5% Ethanol, 50% PEG 200, and 1 equivalent of 2 M HCl:10 mpk (po) by gavage and 5 mpk (iv) as a slow bolus in a tail vein.