title: A novel nonnucleoside analogue that inhibits human immunodeficiency virus type 1 isolates resistant to current nonnucleoside reverse transcriptase inhibitors.
abstract: Nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are important components of current combination therapies for human immunodeficiency virus type 1 (HIV-1) infection. However, their low genetic barriers against resistance development, cross-resistance, and serious side effects can compromise the benefits of the two current drugs in this class (efavirenz and nevirapine). In this study, we report a novel and potent NNRTI, VRX-480773, that inhibits viruses from efavirenz-resistant molecular clones and most NNRTI-resistant clinical HIV-1 isolates tested. In vitro mutation selection experiments revealed that longer times were required for viruses to develop resistance to VRX-480773 than to efavirenz. RT mutations selected by VRX-480773 after 3 months of cell culture in the presence of 1 nM VRX-480773 carried the Y181C mutation, resulting in a less-than-twofold increase in resistance to the compound. A virus containing the double mutation V106I-Y181C emerged after 4 months, causing a sixfold increase in resistance. Viruses containing additional mutations of D123G, F227L, and T369I emerged when the cultures were incubated with increasing concentrations of VRX-480773. Most of the resistant viruses selected by VRX-480773 are susceptible to efavirenz. Oral administration of VRX-480773 to dogs resulted in plasma concentrations that were significantly higher than those required for the inhibition of wild-type and mutant viruses. These results warrant further clinical development of VRX-480773 for the treatment of HIV infection in both NNRTI-naive and -experienced patients.
authors.affiliation: Drug Discovery, Valeant Research and Development, 3300 Hyland Avenue, Costa Mesa, CA 92626, USA. zzhang@valeant.com
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Zhang
authors.forename: Wen
authors.initials: W
authors.lastname: Xu
authors.forename: Yung-Hyo
authors.initials: YH
authors.lastname: Koh
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Shim
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Girardet
authors.forename: Li-Tain
authors.initials: LT
authors.lastname: Yeh
authors.forename: Robert K
authors.initials: RK
authors.lastname: Hamatake
authors.forename: Zhi
authors.initials: Z
authors.lastname: Hong
mesh_terms: D000284:Administration, Oral; D000480:Alkynes; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000627:therapeutic use; D048588:Benzoxazines / Q000494:pharmacology; D002460:Cell Line; D003521:Cyclopropanes; D004285:Dogs; D024882:Drug Resistance, Viral / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D014230:Triazoles; C519971:VRX-480773; C098320:efavirenz