title: Evaluation of hexadecyloxypropyl-9-R-[2-(Phosphonomethoxy)propyl]- adenine, CMX157, as a potential treatment for human immunodeficiency virus type 1 and hepatitis B virus infections.
abstract: 9-R-[2-(Phosphonomethoxy)propyl]-adenine (tenofovir) is an acyclic nucleoside phosphonate with antiviral activity against human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV). Tenofovir is not orally bioavailable but becomes orally active against HIV-1 infection as the disoproxil ester (tenofovir disoproxil fumarate [Viread]). We have developed an alternative strategy for promoting the oral availability of nucleoside phosphonate analogs which involves esterification with a lipid to form a lysolecithin mimic. This mimic can utilize natural lysolecithin uptake pathways in the gut, resulting in high oral availability. Since the mimic is not subject to cleavage in the plasma by nonspecific esterases, it remains intact in the circulation and facilitates uptake by target cells. Significant drops in apparent antiviral 50% effective concentrations (EC(50)s) of up to 3 logs have been observed in comparison with non-lipid-conjugated parent compounds in target cells. We have applied this technology to tenofovir with the goal of increasing oral availability, decreasing the apparent EC(50), and decreasing the potential for nephrotoxicity by reducing the exposure of the kidney to the free dianionic tenofovir. Here we report that, in vitro, the hexadecyloxypropyl ester of tenofovir, CMX157, is 267-fold more active than tenofovir against HIV-1 and 4.5-fold more active against HBV. CMX157 is orally available and has no apparent toxicity when given orally to rats for 7 days at doses of 10, 30, or 100 mg/kg/day. Consequently, CMX157 represents a second-generation tenofovir analog which may have an improved clinical profile.
authors.affiliation: Chimerix Incorporated, Durham, NC 27713, USA.
authors.forename: George R
authors.initials: GR
authors.lastname: Painter
authors.forename: Merrick R
authors.initials: MR
authors.lastname: Almond
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Trost
authors.forename: Bernhard M
authors.initials: BM
authors.lastname: Lampert
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Brent E
authors.initials: BE
authors.lastname: Korba
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Aldern
authors.forename: James R
authors.initials: JR
authors.lastname: Beadle
authors.forename: Karl Y
authors.initials: KY
authors.lastname: Hostetler
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D002460:Cell Line; D005260:Female; D016655:HIV Core Protein p24 / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1; D006509:Hepatitis B / Q000188:drug therapy* / Q000821:virology; D006515:Hepatitis B virus; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D063065:Organophosphonates / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D000068698:Tenofovir
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D016655:HIV Core Protein p24; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D000225:Adenine; C524480:hexadecyloxypropyl 9-(2-(phosphonomethoxy)propyl)adenine