Disease relevance of 1-[(3R,4R,5R)-3,4-dihydroxy-5-methylol-tetrahydrofuran-2-yl]-1,2,4-triazole-3-carboxamidine

• For example, potent and HDV-specific inhibition, in the absence of detected host toxicity, could be obtained with ribavirin, mycophenolic acid, and viramidine [1].
• An investigational nucleoside analogue drug, viramidine, has recently emerged as a potentially safer alternative to ribavirin for the treatment of hepatitis C viral infection [2].
• Ribamidine (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine) was inhibitory in rhesus monkey kidney (LLC-MK2 derivative) cells to Adames and Balliet strains of Punta Toro virus (PTV), a Phlebovirus related to Rift Valley fever and sandfly fever viruses [3].
• In the 1-month study in rats, viramidine or ribavirin dosing at 120 mg/kg/day reduced Hgb concentrations (12-16% and 13-20% compared to controls, respectively) and caused slight erythroid hyperplasia in the bone marrow [4].
• In September 2000, phase I trials began in Europe. In December 2001, the company filed a US IND for the clinical development of viramidine as part of a combination therapy with interferon-afor the treatment of chronic hepatitis C virus (HCV) infection [435007], [441613]; a phase I trial was initiated in the US in late March 2002 [435598] [5].

High impact information on 1-[(3R,4R,5R)-3,4-dihydroxy-5-methylol-tetrahydrofuran-2-yl]-1,2,4-triazole-3-carboxamidine

• The amounts of unchanged viramidine (3.4% of dose) and ribavirin (10% of dose) in urine were small after oral administration of viramidine [6].
• Viramidine and ribavirin accounted for only 4.3% and 42% of plasma area under the concentration-time curve (AUC) for radioactivity, respectively, indicating extensive conversion of viramidine to ribavirin, followed by further metabolism of ribavirin [6].
• The metabolic profile in urine (0 to 24 h) indicated that viramidine was excreted primarily as triazole carboxamide (TCONH2), triazole carboxylic acid nucleoside (TCOOH), and ribavirin with a small amount of unchanged viramidine, which each accounted for 64.1%, 17.0%, 15.7%, and 3.2% of urinary radioactivity, respectively [6].
• Like ribavirin, viramidine was found to be phosphorylated by either adenosine kinase or cytosolic 5'-nucleotidase II, albeit with a much lower activity [7].
• Both ribavirin and viramidine are not phosphorylated by deoxycytidine kinase and uridine-cytidine kinase [7].

Chemical compound and disease context of 1-[(3R,4R,5R)-3,4-dihydroxy-5-methylol-tetrahydrofuran-2-yl]-1,2,4-triazole-3-carboxamidine

• Prospects for hepatitis C virus therapeutics: levovirin and viramidine as improved derivatives of ribavirin [8].

Biological context of 1-[(3R,4R,5R)-3,4-dihydroxy-5-methylol-tetrahydrofuran-2-yl]-1,2,4-triazole-3-carboxamidine

• The current study was carried out to evaluate the safety, tolerability, and pharmacokinetics of viramidine in healthy male volunteers (n = 8-18 on viramidine vs. 2 on placebo at each dose level) after oral dosing of viramidine at 200, 600, and 1200 mg [9].
• Viramidine down-regulated both expressed sequence tag 233569 and heat shock protein 86 genes threefold [10].
• Delay of the initiation of either viramidine or ribavirin therapy, using the approximate 1/3 LD50 dose of each, was protective as late as 48 h after exposure to the A/NWS/33 virus [11].
• Previously we reported that viramidine is a prodrug of ribavirin and that adenosine deaminase catalyses viramidine deamination to ribavirin in vivo [12].

Anatomical context of 1-[(3R,4R,5R)-3,4-dihydroxy-5-methylol-tetrahydrofuran-2-yl]-1,2,4-triazole-3-carboxamidine

• Significant accumulation of viramidine was noted in red blood cells (accumulation factor [R] = 5-8) but not in plasma (R = 2) [13].
• LC-MS/MS method for simultaneous determination of viramidine and ribavirin levels in monkey red blood cells [14].
• Moderate decrease in Hgb levels (26-29%) together with large increase in reticulocyte counts (203-224%) were seen for viramidine at 600 mg/kg/day [4].

Associations of 1-[(3R,4R,5R)-3,4-dihydroxy-5-methylol-tetrahydrofuran-2-yl]-1,2,4-triazole-3-carboxamidine with other chemical compounds

• Following oral administration, viramidine was extensively converted to ribavirin, followed by further metabolism of ribavirin in both species, with a faster rate of metabolism in rats than in monkeys [15].
• A liver-targeting prodrug of ribavirin, viramidine, is in clinical trial in an attempt to provide a better therapeutic index [16].

Gene context of 1-[(3R,4R,5R)-3,4-dihydroxy-5-methylol-tetrahydrofuran-2-yl]-1,2,4-triazole-3-carboxamidine

• Kinetic analysis indicates that adenosine deaminase is likely involved in activation of viramidine in vivo, and the process is highly pH sensitive [16].
• This result suggests that viramidine may act through a dual-action mechanism by serving as a prodrug of ribavirin and concomitantly as an inhibitor for nucleoside phosphorylase catabolism of ribavirin [2].

Analytical, diagnostic and therapeutic context of 1-[(3R,4R,5R)-3,4-dihydroxy-5-methylol-tetrahydrofuran-2-yl]-1,2,4-triazole-3-carboxamidine

• In addition, an evaluation of the effect of a high-fat meal on the pharmacokinetics of viramidine and ribavirin after oral dosing of viramidine at 600 mg was conducted in healthy male volunteers (n = 33-34) in a crossover study design [9].
• In a whole body autoradiography study in rats following oral dosing (30 mg/kg) of [14C]ribavirin or [14C]viramidine to monkeys, viramidine produced 32% higher radioactivity in the liver than ribavirin, indicating a better liver-targeting properties [17].

References