AIDSWEEKLY Plus; Monday, August 24 & 31, 1998
Daniel J. DeNoon, Senior Editor
In vitro studies of the drug suggest that when HIV acquires resistance to the drug, it may lose its ability to infect T cells.
The drug is the bicyclam compound dubbed AMD3100, manufactured by AnorMed, Langley, British Columbia, Canada, in cooperation with Sandoz Research Institute, Vienna, Austria, and Progenics Pharmaceuticals Inc., Tarrytown, New York.
"AMD3100 holds great promise as a candidate anti-HIV drug and clinical Phase I/II trials with the compound have been started," announced Dominique Schols of the Rega Institute, Leuven, Belgium, where the drug was discovered in 1992.
Schols reported data from intensive study of AMD3100 at the 12th World AIDS Conference, held June 28-July 3, 1998, in Geneva, Switzerland.
Interest in the bicyclam compounds recently intensified when it was found that the drugs block the CXCR4, or X4, chemokine receptor needed for HIV to infect T cells.
HIV strains tropic for macrophages (M-tropic strains) predominate in the early stages of HIV infection. These strains use the CCR5 or R5 chemokine receptor for cell entry. Just before patients develop severe immune deficiency, there is a dramatic change and T-cell-tropic HIV strains predominate.
AMD3100 does not affect M-tropic HIV-1 strains, although it is one of the most potent anti-HIV compounds yet found against T-tropic HIV-1 and HIV-2. The drug is effective at sub-nanomolar concentrations. Interestingly, HIV that has become resistant to AMD3100 does not switch to R5 receptor use, Schols said.
She noted that the drug affects no other chemokine receptors, and that it does not initiate signal transduction when it binds to the X4 receptor. Even at high concentrations the drug has no chemotactic activity. However, Schols reported that the drug does prevent chemotactic responses induced by the receptor's normal chemokine ligand, SDF-1.
Even as clinical tests of AMD3100 begin, a new version of the drug is on the way.
In another AIDS conference presentation, Jose A. Este of Irsi- Caixa, Badalona, Spain, reported that a new N-benzyl cyclam is 10 times more potent than AMD3100 in vitro.
The new drug, dubbed AMD3465, contains only one cyclam ring (AMD3100 has two) and has a pyrimidine moiety linked via a phenyl bridge. Like AMD3100, it specifically blocks the X4 chemokine receptor. Preclinical development of the compound is underway.
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