Efficacy, pharmacokinetics, and in vivo antiviral activity of UC781, a highly potent, orally bioavailable nonnucleoside reverse transcriptase inhibitor of HIV type 1.
A series of compounds related to oxathiin carboxanilide has been identified as nonnucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1, and structure-activity relationships have been described (Buckheit RW, et al.: Antimicrob Agents Chemother 1995;39:2718-2727). Three new analogs (UC040, UC82, and UC781) inhibited laboratory and clinical isolates of HIV-1, including isolates representative of the various clades of HIV-1 found worldwide, in both established and fresh human cells. Virus isolates with the amino acid changes L100I, K103N, V106I, and Y181C in the reverse transcriptase were partially resistant to these compounds. However, UC781 inhibited these virus isolates at low nontoxic concentrations, presenting a broad in vitro therapeutic index. As with other NNRTIs, each of the compounds synergistically interacted with AZT to inhibit HIV-1 replication. UC781 possesses a favorable pharmacokinetic profile in mice with a high level of oral bioavailability. Plasma concentrations reached maximum levels within 2 to 4 hr of oral administration and remained in excess of those required for in vitro anti-HIV activity for at least 24 hr after a single oral dose. When evaluated in a murine hollow fiber implant model of HIV infection, UC781 dosed orally or parenterally was able to suppress HIV replication completely in this model system, providing evidence of the in vivo efficacy of the compound.
Buckheit
R W
RW
Virology Research Group, Southern Research Institute-Frederick Research Center, Maryland 21701, USA.
Hollingshead
M
M
Stinson
S
S
Fliakas-Boltz
V
V
Pallansch
L A
LA
Roberson
J
J
Decker
W
W
Elder
C
C
Borgel
S
S
Bonomi
C
C
Shores
R
R
Siford
T
T
Malspeis
L
L
Bader
J P
JP
D000284:Administration, Oral; D000813:Anilides / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001682:Biological Availability; D005663:Furans / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016655:HIV Core Protein p24 / Q000032:analysis; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D015498:HIV-2 / Q000187:drug effects*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008815:Mice, Inbred Strains; D008826:Microbial Sensitivity Tests; D017354:Point Mutation; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D013854:Thioamides
D000813:Anilides; D019380:Anti-HIV Agents; D005663:Furans; D016655:HIV Core Protein p24; D018894:Reverse Transcriptase Inhibitors; D013854:Thioamides; D054303:HIV Reverse Transcriptase; C100668:UC-781