Chemokine receptor antagonists/inhibitors

The gold-standard assay used for all chemokine receptor inhibitors that reach clinical-phase trials is the chemotaxis functional assay. This assay relies on the ability of chemokines to recruit cells expressing their respective receptor to areas of inflammation. In vitro, this assay was first described in detail by Taub et al. (16) for 24/48-well plates currently, this can be achieved by using 96-well plates. Cells are incubated in the upper chamber with an antagonist for a particular receptor (at different concentrations or with buffer) and challenged to migrate to the lower chamber, which has the relevant chemokine. After 2 to 4 hours of incubation at 37°C, the upper chamber inlet is removed and the cells in the lower chamber quantified by fluorescence with, for example, Calcein AM (Invitrogen, Carlsbad, CA). 

Inhibitors of translation of viral mRNA (antisense oligonucleotides) Inhibitors of posttranslational glycosylation Antagonists of chemokine receptors... 

The chiral sulfoxide 354 was shown to be one of a number of potent CC chemokine receptor 5 antagonists (IC50 1.9 nM) and a potent inhibitor (ICS0 1.0nM) in the HIV-1 envelope mediated membrane fusion assay. This compound also exhibited favorable oral absorption characteristics in rats making it a promising lead for further development as an anti-HIV agent <2005BMC363>. 

Dorr, P., Macartney, M., Rickett, G., Smith-Burchnell, C., Dobbs, S., Mori, J., Griffin, P., Lok, J., Irvin, R., Westby, M., Hitchcock, C., Stammen, B., Price, D., Armour, D., Wood, A., and Perros, M. (2003). UK-427,857, a novel small molecule HIV entry inhibitor is a specific antagonist of the chemokine receptor CCR5. In 10th Conference on Retroviruses and Opportunistic Infections. Boston, MA. 

---