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1st International Workshop on HIV Drug Resistance & Treatment Strategies25-28 June 1997, St. Petersburg, Florida, USA |
THERAPEUTIC POTENTIAL OF OXATHIIN CARBOXANILIDE ANALOGUES: IN VITRO AND IN VIVO EFFICACY, PHARMACOKINETICS AND RESISTANCE
Antiviral Therapy 1997;2 (Suppl 5):3 (abstract no. 6)
RW Buckheit Jr1, TL Stup1, TL Kinjerski1, Hollingshead2 and S Stinson2
1Southern Research Institute; and 2National Cancer Institute, Frederick, Maryland, USA
Structure-activity relationships of a series of compounds related to the non-nucleoside reverse transcriptase (RT) inhibitor (NNRTI) oxathiin carboxanilide (UC84) have been described. The efficacy of a variety of highly potent compounds have been described. Four UC compounds were selected for further preclinical evaluation based on their inhibitory activity at low nanomolar concentrations, their ability to inhibit the replication of NNRTI-resistant viruses and their wide therapeutic indices. These UC compounds exhibit antiviral properties which suggest they may be useful in the treatment of HIV disease. (1) The broad therapeutic index of several of the compounds (UC781: >62,000) yields effective inhibition of NNRTI-resistant virus isolates at sub-micromolar concentrations. (2) All of the UC compounds interact synergistically with the nucleoside analogues and additively with the protease inhibitors. Unlike most of the NNRTIs, several of the UC compounds interact synergistically with other NNRTIs, suggesting they may interact in a different mechanistic fashion with the RT. (3) UC-resistant viruses selected in cell culture vary in their overall level of resistance, in their cross-resistance to other NNRTIs and in the amino acid change present in the RT. (4) The UC compounds may select for resistant viruses at different rates and to relatively different levels of resistance, offering the possibility of selecting compounds for use which do not readily result in high levels of drug resistance. (5) Several UC compounds (UC781 and UC10) possess favourable pharmacokinetic profiles in mice with a high level of oral bioavailability. Plasma concentrations reached maximum levels within 2- 4 h of administration and remained in excess of those required for in vitro anti-HIV activity for at least 24 h after a single oral dose. (6) When evaluated in a murine hollow fibre implant model of HIV infection, UC781 dosed orally or parenterally was able to completely suppress HIV replication, providing evidence of in vivo efficacy. In conclusion, our preclinical anti-HIV evaluations suggest that several of the UC analogues merit further consideration for use in patients. We propose that the UC compounds may be effectively used in combination with nucleoside analogues as a first line of antiviral therapy in infected patients, as well as in cases of needle stick injuries and in combination with microbicides to prevent the sexual transmission of HIV.
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1997-06-25
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