Denavir
Synthesis and evaluation of 2-amino-9-(3-acyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purines and 2-amino-9-(3-alkoxycarbonyloxymethyl-4-alkoxycarbonyloxybut-1- yl)purines as potential prodrugs of penciclovir.

Kim DK, Lee N, Ryu DH, Kim YW, Kim JS, Chang K, Im GJ, Choi WS, Cho YB, Kim KH, Colledge D, Locarnini S.

Life Science Research Center, SK Chemicals, Kyungki-Do, Korea. dkkim skchemicals.com

A series of 2-amino-9-(3-acyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purin es (1-8) and 2-amino-9-(3-alkoxycarbonyl-oxymethyl-4-alkoxycarbonyloxybut -1-yl)purines (9-12) were synthesized as potential prodrugs of penciclovir. Treatment of 6-deoxypenciclovir with trimethyl orthoacetate or triethyl orthopropionate (1.2 equiv) in DMF in the presence of p-TsOH.H2O (0.1 equiv) followed by quenching with excess H2O gave the corresponding mono-O-acetyl or mono-O-propionyl compound, 17 or 18, in excellent yields of 95 and 92%, respectively. Reactions of 17 or 18 with an appropriate alkyl (Me, Et, n-Pr, and i-Pr) 4-nitrophenyl carbonate (1.2 equiv) in pyridine in the presence of a catalytic amount of DMAP (0.1 equiv) at 80 degrees C afforded the monoacyl, monocarbonate derivatives of 6-deoxypenciclovir, 1-8, in 86 94% yields. Similar reactions of 6-deoxypenciclovir with 2.1 equiv of alkyl 4-nitrophenyl carbonate produced the dicarbonate derivatives 9 12 in 81-83% yields. Of the prodrugs tested in rats, 2-amino-9-(3-acetoxymethyl-4-isopropoxycarbonyloxybut-1-yl)purine (4) achieved the highest mean urinary recovery of penciclovir (36%), followed in order by compounds 2 (35%), 6 (35%), 7 (34%), 10 (34%), 8 (32%), 3 (32%), and famciclovir (31%). The mean urinary recovery of penciclovir and concentrations of penciclovir in the blood from 4 in mice were also slightly higher than those from famciclovir. The in vivo antiviral efficacy of 4 in HSV-1-infected normal BALB/c mice was higher than those of famciclovir and valaciclovir in terms of mortality (100, 80, and 40%) and mean survival time ( > 21, 13+/-5.0 (SEM), and 13+/-1.6 days). Compound 4 demonstrated an effective anti-hepadnaviral response with intrahepatic viral load being reduced by 90%, the viral supercoiled DNA levels reduced by 70% and Pre-S expression inhibited by 30% against duck hepatitis B virus (DHBV) in vivo, and did not cause any significant hepatotoxicity after 4 weeks of treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10482463&dopt=Abstract penciclovir Denavir



Denavir
Genotypic characterization of the DNA polymerase and sensitivity to antiviral compounds of foscarnet-resistant herpes simplex virus type 1 (HSV-1) derived from a foscarnet-sensitive HSV-1 strain.

Saijo M, Suzutani T, Morikawa S, Kurane I.

Special Pathogens Laboratory, Department of Virology 1, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo 208-0011, Japan. msaijo nih.go.jp

Foscarnet is widely used for the treatment of acyclovir-resistant herpesvirus infections, and foscarnet-resistant herpesvirus infections are a serious concern in immunocompromised patients. Twenty-seven single-plaque isolates of herpes simplex virus type 1 (HSV-1) resistant to foscarnet were selected from foscarnet- and acyclovir-sensitive HSV-1 strain TAS by exposure to foscarnet, and the DNA polymerase genes were analyzed. The sensitivities of these mutants to foscarnet, cidofovir, S2242, acyclovir, ganciclovir, and penciclovir were determined. A single amino acid substitution, double amino acid substitutions, and a combination of a single amino acid substitution with a deletion or insertion of amino acid residues in the viral DNA polymerase were demonstrated in 21, 4, and 2 isolates, respectively. Of the 27 isolates, an amino acid substitution of serine for asparagine at amino acid position 724 in the DNA polymerase (724 S-N) was detected in 8 isolates. An amino acid substitution in conserved region II was demonstrated in these eight isolates as well as four other isolates. The mutation in the DNA polymerase responsible for resistance to foscarnet was located between the pre-IV region and conserved region V, especially within conserved region II. All the isolates were sensitive or hypersensitive to cidofovir and ganciclovir. Seven, 5, and 15 of the 27 isolates were also sensitive to S2242, acyclovir, and penciclovir, respectively. Thus, most of the foscarnet-resistant HSV-1 isolates were sensitive or hypersensitive to cidofovir and ganciclovir.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15673740&dopt=Abstract penciclovir Denavir



Denavir
Selection of an oral prodrug (BRL 42810; famciclovir) for the antiherpesvirus agent BRL 39123 [9-(4-hydroxy-3-hydroxymethylbut-l-yl)guanine; penciclovir].

Vere Hodge RA, Sutton D, Boyd MR, Harnden MR, Jarvest RL.

Beecham Pharmaeuticals Research Division, Biosciences Research Centre, Epsom, Surrey, England.

The limited oral absorption in rodents of the antiherpesvirus agent 9-(4-hydroxy-3-hydroxymethylbut-l-yl)guanine (BRL 39123 [penciclovir; British approved name]) prompted a search for oral prodrugs. The 6-deoxy derivative of penciclovir (BRL 42359) and the corresponding diacetyl and dipropionyl 6-deoxy derivatives (BRL 42810 [famciclovir; British approved name] and BRL 43599) were tested as oral prodrugs. The in vivo absorption (dose, 0.2 mmol/kg) and the conversion to the active compound, penciclovir, were determined in rats. Compared with the sodium salt of penciclovir given intravenously, the bioavailabilities of penciclovir from orally administered penciclovir, BRL 42359, famciclovir, and BRL 43599 were 1.5, 9, 41, and 27%, respectively. These prodrugs and 6-deoxyacyclovir were tested for stability in rat duodenal contents and for metabolism in rat intestinal wall homogenate, liver homogenate, and blood and in the corresponding human fluids and tissues. Famciclovir was much more stable than BRL 43599 in human duodenal contents (half-lives, greater than 2 h and 7 min, respectively) yet was efficiently converted to penciclovir by the tissue homogenates. The major metabolic pathway was by deacetylation followed by oxidation at the 6 position. The rate of oxidation was comparable to that of 6-deoxyacyclovir, which is known to be converted efficiently to acyclovir in humans. Famciclovir was selected for further evaluation and progression to studies in humans. These subsequent studies confirmed that, after oral dosing with famciclovir, more than half the dose was absorbed and rapidly converted to penciclovir.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2589844&dopt=Abstract penciclovir Denavir



Denavir
Activity of penciclovir against Epstein-Barr virus.

Bacon TH, Boyd MR.

SmithKline Beecham Pharmaceuticals, Betchworth, Surrey, United Kingdom.

Penciclovir inhibited the productive replication cycle of Epstein-Barr virus (EBV) in assays measuring infectious virus production, viral antigen expression, and viral DNA synthesis. In the test measuring inhibition of EBV DNA synthesis, 50% effective concentrations of penciclovir and acyclovir were 2.3 +/- 0.8 and 2.2 +/- 0.6 micrograms/ml, respectively. The 50% cell growth inhibitory concentration of penciclovir was > 100 micrograms/ml for both P3HR-1 and Raji cells. Penciclovir is a selective inhibitor of EBV in cell culture.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7492112&dopt=Abstract penciclovir Denavir



Denavir
Metabolic and pharmacokinetic studies following oral administration of famciclovir to the rat and dog.

Filer CW, Ramji JV, Allen GD, Brown TA, Fowles SE, Hollis FJ, Mort EE.

Drug Metabolism and Pharmacokinetics Department, SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, UK.

1. Drug-related material was well absorbed following oral administration of 14C-famciclovir to the male rat at doses up to 4000 mg/kg and to the male dog at doses up to 250 mg/kg, as judged by the early onset of the peak blood or plasma concentrations of radioactivity (usually < or = 1.5h) and the rapid extensive excretion of radioactivity in the urine (57-76 and 86-89% of dose in rat and dog respectively). 2. Famciclovir underwent extensive first-pass metabolism in both species. In rat, following dosing at 40 mg/kg, famciclovir was rapidly and extensively metabolized to the active antiviral compound penciclovir, which reached peak concentrations in the plasma (mean 3.5 micrograms/ml) at 0.5 h. The 6-deoxy precursor of penciclovir, BRL 42359, was the only other major metabolite detected in rat plasma. Cmax values for BRL 42359 (mean 2.2 micrograms/ml) were also achieved at 0.5 h. In dog, extensive conversion of famciclovir to penciclovir, via BRL 42359, also occurred, but its rate of formation from BRL 42359 was somewhat slower than in rat. In dog, following dosing at 25 mg/kg, Cmax values for penciclovir (mean 4.4 micrograms/ml) occurred at 3 h and were lower than the Cmax values for BRL 42359 (mean 10.0 micrograms/ml) which were achieved at 1h. 3. A dose-dependent decrease in the conversion of BRL 42359 to penciclovir occurred in both species, resulting a changes in the ratios of the plasma concentrations of the two metabolites with increasing dose. In rat, the urinary excretion of penciclovir decreased from 36% of dose at 40 mg/kg to 21% at 4000 mg/kg, and was accompanied by a corresponding increase in the urinary excretion of BRL 42359. In dog, a similar decrease in the urinary excretion of penciclovir occurred on increasing the dose of famciclovir from 25 to 250 mg/kg. 4. Penciclovir and BRL 42359 were the major metabolites detected in urine and faeces. In rat, following dosing at 40 mg/kg, 54 and 22% of dose were recovered in the excreta as penciclovir and BRL 42359 respectively. Corresponding recoveries of the two metabolites in the dog were 34 and 50% of dose. The metabolic fate of famciclovir in these animal species is, therefore, similar to that reported previously in man.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7571721&dopt=Abstract penciclovir Denavir