AIDS Treatment News #159, September 18, 1992
John S. James
* In laboratory tests it is effective against HIV-1 at very small concentrations, a few nanograms per ml. It also has an unusually large ratio (about 1 to 50,000) between the concentration effective against HIV and that which is toxic to cells.
* R89439 has been through standard animal toxicity tests and has been tested in people, in a few HIV-negative volunteers. It is orally available and will probably need to be taken only once or twice a day; eight hours after taking a single 100 mg dose, blood levels in humans are 30 times the amount needed to inhibit HIV. No particular toxicity is expected, although toxicity cannot be ruled out. Laboratory tests suggest that the drug is synergistic when combined with AZT or with ddI.
* Some alpha-APA derivatives are relatively easy to manufacture, and could be available in any country in the world.
The alpha-APA derivatives act by inhibiting reverse transcriptase and are very specific to HIV-1, which suggests that resistance may develop to this class of compounds, as it has with other drugs that are specifically targeted at the HIV-1 reverse transcriptase. At this time, however, no one knows how serious any resistance problem might be.
Alpha-APA (R89439) will next be tested in phase I/II trials in several European countries.
(AIDS TREATMENT NEWS article includes structural formula of R89439 here.)
References
Pauwels R, Andries K, Debyser Z, Van Daele P, Schols D, Janssen MAC, Desmyter J, De Clercq E, and Janssen PAJ. HIV-1 specific phenylacetamide derivatives: A novel class of reverse transcriptase inhibitors with potent and selective antiviral activity in vitro. Fifth International Conference on Antiviral Research, Vancouver, March 8-13, 1992; abstract published in Antiviral Research, Supplement 1, March 1992 [abstract #5, page 45].
Pauwels R, Andries K, Schols D, Van Daele P, Debyset Z, Janssen MAC, Vandamme A, De Vreese K, Desmyter J, De Clercq E, and Janssen PAJ. Potent and highly selective HIV-1 specific inhibition by a new series of alpha-anilino phenylacetamide (alpha-APA) derivatives targeted at HIV-1 RT. VIII International Conference on AIDS, Amsterdam, June 19-24, 1992 [abstract # PoA 2320].
Janssen PAJ, Stoffels P, Andries K, Van Daele P, Woestenborghs R, Pauwels R, Heykants J, Mesens J, Cauwenbergh G, Desmyter J, De Clercq E, and Janssen MAC. Inhibition of HIV-1 by a new series of alpha-anilino phenyl acetamide (alpha-APA) derivatives. VIII International Conference on AIDS, Amsterdam, June 19-24, 1992 [abstract # PoB 3020].
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