2-Amino-6-arylthio-9-[2-(phosphonomethoxy)ethyl]purine Bis(2,2,2-trifluoroethyl) Esters as Novel HBV-Specific Antiviral Reagents

• Published in: Journal of medicinal chemistry Vol. 45; no. 14; pp. 3138 - 3142
• Main Authors: Sekiya, Kouichi, Takashima, Hideaki, Ueda, Naoko, Kamiya, Naohiro, Yuasa, Satoshi, Fujimura, Yoshiyuki, Ubasawa, Masaru
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 04.07.2002; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Line; Chemistry, Medicinal; Hepatitis B virus - drug effects; Intestinal Absorption; Life Sciences & Biomedicine; Liver - metabolism; Male; Medical sciences; Mice; Mice, Inbred C57BL; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Purines - chemical synthesis; Purines - chemistry; Purines - pharmacology; Science & Technology; Structure-Activity Relationship; NUCLEOTIDE ANALOGS; LAMIVUDINE; 9-(2-PHOSPHONYLMETHOXYETHYL)ADENINE; PURINE; DERIVATIVES; CHRONIC HEPATITIS-B; Purine nucleotide; Ether; Liver; Rodentia; Oral administration; Orthohepadnavirus; Organic phosphonate; Bioavailability; In vitro; Virus; In vivo; Tissue; Vertebrata; Mammalia; Structure activity relation; Mouse; Hepadnaviridae; Animal; Distribution; Antiviral; Fluorine Organic compounds; Hepatitis B virus; Pharmacokinetics; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm020036x

Novel 2-amino-6-arylthio-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) esters were synthesized and evaluated for antihepatitis B virus (HBV) activity in vitro using HB611, HuH-6 cell line, stably transfected with the HBV genome. Among the compounds synthesized, 2-amino-6-phenylthio-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester (8), 2-amino-6-(4-methoxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester (16), 2-amino-6-(3-methoxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester (17), and 2-amino-6-(2-methoxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester (18) showed considerably high anti-HBV activity, as represented by IC50 values of 0.05, 0.03, 0.04, and 0.08 μM, respectively, and exhibited low cytotoxicity, as represented by CC50 values of more than 1000 μM. It was suggested that these compounds did not have anti-HIV activity, and compound 8 showed only weak anti-HSV-1 activity. An antiviral agent, 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA), which was used as a control in the present study, showed moderate anti-HBV activity, as represented by an IC50 value of 0.2 μM. Furthermore, compound 16 was administered orally to mice at a dose of 100 mg/kg in order to examine its gastrointestinal absorbability. Consequently, the main active metabolite was observed in mouse plasma, with especially high concentrations in the liver.