title: Biological and biochemical anti-human immunodeficiency virus activity of UC 38, a new non-nucleoside reverse transcriptase inhibitor.
abstract: UC 38, a simple analog of oxathiin carboxanilide, UC 84, lacking the oxathiin ring, was found to be a potent inhibitor of human immunodeficiency virus (HIV)-1-induced cell killing and HIV replication in a variety of human cell lines, as well as in human peripheral blood lymphocytes and macrophages. UC 38 was active against a wide range of biologically diverse laboratory and clinical strains of HIV-1. However, UC 38 was inactive against HIV-2 and both nevirapine- and pyridinone-resistant strains of HIV-1. UC 38 selectively inhibited HIV-1 reverse transcriptase (RT), but not HIV-2 RT. Combination of UC 38 with 3'-azido-3'-deoxythymidine synergistically inhibited HIV-induced cell killing. An HIV-1 isolate resistant to UC 38 was selected in cell culture, and the mutations in the RT nucleotide sequences were determined. Comparison with the wild-type RT sequence revealed an amino acid change at position 181 (Tyr to Cys). The UC 38-resistant virus was found to be cross-resistant to a variety of structurally diverse non-nucleoside RT inhibitors. UC 38 was susceptible to rapid degradation in vitro and in vivo; yet, nontoxic in vivo concentrations of UC 38 many-fold in excess of the in vitro effective concentrations could be achieved and maintained after s.c. or p.o. administration in hamsters. These results establish UC 38 as a new chemotype within the general class of HIV-1-specific RT inhibitors. The favorable physical characteristics, lack of toxicity, potency and bioavailability of UC 38 may make it a candidate for combination chemotherapy of acquired immune deficiency syndrome.
authors.affiliation: Laboratory of Drug Discovery Research and Development, National Cancer Institute, Frederick, Maryland, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: McMahon
authors.forename: R W
authors.initials: RW
authors.lastname: Buckheit
authors.forename: R J
authors.initials: RJ
authors.lastname: Gulakowski
authors.forename: M J
authors.initials: MJ
authors.lastname: Currens
authors.forename: D T
authors.initials: DT
authors.lastname: Vistica
authors.forename: R H
authors.initials: RH
authors.lastname: Shoemaker
authors.forename: S F
authors.initials: SF
authors.lastname: Stinson
authors.forename: J D
authors.initials: JD
authors.lastname: Russell
authors.forename: J P
authors.initials: JP
authors.lastname: Bader
authors.forename: V L
authors.initials: VL
authors.lastname: Narayanan
authors.forename: R J
authors.initials: RJ
authors.lastname: Schultz
authors.forename: W G
authors.initials: WG
authors.lastname: Brouwer
authors.forename: E E
authors.initials: EE
authors.lastname: Felauer
authors.forename: M R
authors.initials: MR
authors.lastname: Boyd
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001565:Benzoates / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D002261:Carboxin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D006224:Cricetinae; D004252:DNA Mutational Analysis; D004279:DNA, Viral / Q000032:analysis / Q000235:genetics; D004334:Drug Administration Schedule; D004352:Drug Resistance, Microbial; D004355:Drug Stability; D004357:Drug Synergism; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D012194:RNA-Directed DNA Polymerase / Q000187:drug effects*; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D013859:Thiocarbamates / Q000493:pharmacokinetics / Q000494:pharmacology*; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D001565:Benzoates; D004279:DNA, Viral; C070134:NSC 615985; D018894:Reverse Transcriptase Inhibitors; D013859:Thiocarbamates; C083308:NSC 629243; D015215:Zidovudine; D002261:Carboxin; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase