Chemokine Receptor Inhibitor

Princen K, Schols D. HIV chemokine receptor inhibitors as novel anti-HIV drugs. Cytokine Growth Factor Rev 2005 16(6) 659-677. 

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). 

Figure 13.8 Asymmetric reduction of4,4-dimethoxytetrahydro-2H-pyran-3-one to (R)-4,4-dimethoxytetrahydro-2H-pyran-3-ol for the total synthesis of a chemokine receptor inhibitor.

Bertini R, Allegretti M, Bizzarri C, et al. Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2 prevention of reperfusion injury. Proc Natl Acad Sci U S A 2004 101 11791-11796. 

Dorr P, Westby M, Dobbs S, et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Anti-microb Agents Chemother 2005 49(l 1 ) 4721 —4732. 

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>. 

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