Efficacy, pharmacokinetics, and in vivo antiviral activity of UC781, a highly potent, orally bioavailable nonnucleoside reverse transcriptase inhibitor of HIV type 1
作者： ROBERT W. BUCKHEIT , MELINDA HOLLINGSHEAD , SHERMAN STINSON , VALERIE FLIAKAS-BOLTZ , LUKE A. PALLANSCH
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摘要: A series of compounds related to oxathiin carboxanilide has been identified as nonnucleoside reverse transcriptase inhibitors (NNRTIs) HIV-1, and structure-activity relationships have described (Buckheit RW, et al.: Antimicrob Agents Chemother 1995;39:2718-2727). Three new analogs (UC040, UC82, UC781) inhibited laboratory clinical isolates including representative the various clades HIV-1 found worldwide, in both established fresh human cells. Virus with amino acid changes L100I, K103N, V106I, Y181C were partially resistant these compounds. However, UC781 virus at low nontoxic concentrations, presenting a broad vitro therapeutic index. As other NNRTIs, each synergistically interacted AZT inhibit replication. possesses favorable pharmacokinetic profile mice high level oral bioavailability. Plasma concentrations reached maximum levels within 2 4 hr administration remained excess those required for anti-HIV activity least 24 after single dose. When evaluated murine hollow fiber implant model HIV infection, dosed orally or parenterally was able suppress replication completely this system, providing evidence vivo efficacy compound.
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