Phosphonylmethoxyalkyl purine and pyrimidine derivatives for treatment of opportunistic cytomegalovirus and herpes simplex virus infections in murine AIDS

Castro, Laura M. De; Kern, Earl R.; Clercq, Erik De; Ghaffar, Abdul; Mayer, Eugene P.; Vogt, Peggy E.; Gangemi, J. David

doi:10.1016/0166-3542(91)90062-v

Cited by 28 publications

(9 citation statements)

References 30 publications

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“…However, their selectivity indices were inferior to that of PMEA and PMEDAP. PMEA and PMEDAP have been found inhibitory to human immunodeficiency virus (HIV) and other retroviruses, both in vitro and in vivo (Pauwels et al, 1988;Gangemi et aI., 1989;Naesens et aI., 1989Naesens et aI., , 1991Balzarini et aI., 1990Balzarini et aI., , 1991aBalzarini et aI., , 1991bEgberink ef aI., 1990;De Castro et et., 1991;Del Gobbo et al, 1991;Hoover et al, 1991). A single dose of PMEA or PMEDAP, when administered shortly before or after Moloney murine sarcoma virus 'Concentration required to inhibit enzymatic activity by 50%.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of Acyclic Nucleoside Phosphonate Analogues on Hepatitis B Virus DNA Synthesis in HB611 Cells

Yokota¹,

Konno²,

Shigeta

et al. 1994

Antivir Chem Chemother

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SummaryBy using an assay system based on a human hepatoblastoma cell line (HB611) that continuously synthesizes hepatitis B virus (HBV) DNA, 56 acyclic nucleoside phosphonate analogues were examined for their inhibitory effects on HBV DNA synthesis. The following compounds were found to inhibit HBV DNA synthesis at concentrations that were significantly lower than their minimum cytotoxic concentrations; 9-(2-phosphonylmethoxyethyl)adenine (PMEA), 9-(2-phosphonylmethoxyethyl) guanine(PMEG), 9-(2-phosphonylmethoxyethyl) guanine ethyl ester (PMEGEE), 9 -(2 -phosphonylmethoxyethyQ -1 -deazaadenine (PMEC 1A), 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP), (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (HPMPA), 9-(3-isopropoxy-2-phosphonylmethoxypropyl)adenine (IPPMPA), 9-(RS)-(2-phosphonylmethoxypropyl)adenine (PMPA) and 9-(3-hydroxy-2-phosphonylmethoxypropyl)-2, 6-diaminopurine (HPMPDAP). The most selective compounds (with indexes greater than 100) were PMEDAP, PMEA, IPPMPA, and PMPA. Acyclic pyrimidine nucleoside phosphonate analogues did not prove markedly selective as anti-HBV agents. Diphosphoryl derivatives of some acyclic purine nucleoside phosphonates (i.e. PMEA, PMEDAP, HPMPA) were prepared. They proved inhibitory to HBV DNA polymerase but not cellular DNA polymerase ct.

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Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of Acyclic Nucleoside Phosphonate Analogues on Hepatitis B Virus DNA Synthesis in HB611 Cells

Yokota¹,

Konno²,

Shigeta

et al. 1994

Antivir Chem Chemother

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“…Among these drugs, adefovir (PMEA) is a broad-spectrum nucleotide analogue that acts against HIV, herpesviruses, and hepadnaviruses (13)(14)(15)(16). Adefovir dipivoxil (the oral prodrug of PMEA) is in clinical trials for use in the treatment of HIV and HBV infection (15,16).…”

Section: Introductionmentioning

confidence: 99%

Susceptibility of lamivudine-resistant hepatitis B virus to other reverse transcriptase inhibitors

Ono‐Nita

Kato²,

Shiratori³

et al. 1999

J. Clin. Invest.

128

101

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“…Eligible subjects included HIV-infected per-15 mL of 50% (wt/wt) chloroacetaldehyde in water. The serum method was linear over the range 250-15,000 ng/mL, and the sons with CD4 cell counts of at least 100/mm 3 analysis and only the dose groups of adefovir dipivoxil were tration (C max ), the time to C max (T max ), AUC extrapolated to infinity, compared, no significant dose-dependent effect was seen. and the half-life of the terminal elimination phase (t 1/2 ).…”

mentioning

confidence: 99%

Anti‐Human Immunodeficiency Virus (HIV) Activity, Safety, and Pharmacokinetics of Adefovir Dipivoxil (9‐[2‐(bis‐pivaloyloxymethyl)‐phosphonylmethoxyethyl]adenine) in HIV‐Infected Patients

Barditch‐Crovo

Toole²,

Hendrix³

et al. 1997

J INFECT DIS

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A randomized, double-blind, placebo-controlled, dose-escalation study of adefovir dipivoxil, an oral prodrug of adefovir, was conducted in 36 human immunodeficiency virus (HIV)-infected subjects to evaluate its anti-HIV activity, safety, and pharmacokinetics. Subjects received placebo or one of three dosages of adefovir dipivoxil daily for 14 days. Median decreases in serum p24 antigen of 31% (P = .02), 25% (P = .31), and 30% (P = .01) occurred in each drug-treated group, respectively, compared with an increase of 17% in the placebo group. Median decreases in serum HIV RNA of 0.4-0.6 log10 copies/mL occurred in the drug-treated groups (P = .03), compared with no change in the placebo group. Gastrointestinal complaints and reversible liver transaminase elevations were the most frequently noted adverse events. Decreases in serum free carnitine occurred in each drug-treated group during treatment. After 14 days of dosing, adefovir dipivoxil demonstrated anti-HIV activity and was best tolerated at the lowest dosage studied, 125 mg daily.

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Phosphonylmethoxyalkyl purine and pyrimidine derivatives for treatment of opportunistic cytomegalovirus and herpes simplex virus infections in murine AIDS

Cited by 28 publications

References 30 publications

Inhibitory Effects of Acyclic Nucleoside Phosphonate Analogues on Hepatitis B Virus DNA Synthesis in HB611 Cells

Inhibitory Effects of Acyclic Nucleoside Phosphonate Analogues on Hepatitis B Virus DNA Synthesis in HB611 Cells

Susceptibility of lamivudine-resistant hepatitis B virus to other reverse transcriptase inhibitors

Anti‐Human Immunodeficiency Virus (HIV) Activity, Safety, and Pharmacokinetics of Adefovir Dipivoxil (9‐[2‐(bis‐pivaloyloxymethyl)‐phosphonylmethoxyethyl]adenine) in HIV‐Infected Patients

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