title: Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
abstract: CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
authors.affiliation: Chimerix Inc., 2505 Meridian Parkway, Suite 340, Durham, NC 27713, USA. rlanier@chimerix-inc.com
authors.forename: E Randall
authors.initials: ER
authors.lastname: Lanier
authors.forename: Roger G
authors.initials: RG
authors.lastname: Ptak
authors.forename: Bernhard M
authors.initials: BM
authors.lastname: Lampert
authors.forename: Laurie
authors.initials: L
authors.lastname: Keilholz
authors.forename: Tracy
authors.initials: T
authors.lastname: Hartman
authors.forename: Robert W
authors.initials: RW
authors.lastname: Buckheit
authors.forename: Marie K
authors.initials: MK
authors.lastname: Mankowski
authors.forename: Mark C
authors.initials: MC
authors.lastname: Osterling
authors.forename: Merrick R
authors.initials: MR
authors.lastname: Almond
authors.forename: George R
authors.initials: GR
authors.lastname: Painter
mesh_terms: D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D024882:Drug Resistance, Viral / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008264:Macrophages / Q000821:virology; D009705:Nucleosides / Q000627:therapeutic use*; D009711:Nucleotides / Q000627:therapeutic use*; D063065:Organophosphonates / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000068698:Tenofovir
chemical_list: D019380:Anti-HIV Agents; D009705:Nucleosides; D009711:Nucleotides; D063065:Organophosphonates; D000068698:Tenofovir; D000225:Adenine; C524480:hexadecyloxypropyl 9-(2-(phosphonomethoxy)propyl)adenine