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Chemical Compound Review:

Apricitabine 4-amino-1-[(2R,4R)-2- (hydroxymethyl)-1,3...

Synonyms: AVX-754, BCH-270, SPD-754, AVX754, SPD754, ...

de Muys, J.M. et al., Richar, N. et al., Taylor, D.L. et al., Gu, Z. et al., Smith, P.F. et al., et al.

Taylor, Ahmed, Tyms, Wood, Kelly, Chambers, Clarke, Bedard, Bowlin, Rando, Stoddart, Moreno, Linquist-Stepps, Bare, Bogan, Gobbi, Buckheit, Bedard, Rando, McCune, Smith, Forrest, Ballow, Martin, Proulx, Smith, Forrest, Ballow, Martin, Proulx, Cahn, Cassetti, Wood, Phanuphak, Shiveley, Bethell, Sawyer,

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Disease relevance of trans-Oxathiolan-C

Selection and characterization of HIV-1 variants resistant to the (+) and (-) enantiomers of 2'-deoxy-3'-oxa-4'-thiocytidine (dOTC) [1].
OBJECTIVE: Apricitabine (formerly AVX754 and SPD754) is a deoxycytidine analogue nucleoside reverse transcriptase inhibitor in clinical development for patients with HIV disease [2].
Anti-human immunodeficiency virus and anti-hepatitis-B virus activities and toxicities of the enantiomers of 2'-deoxy-3'-oxa-4'-thiocytidine and their 5-fluoro analogues in vitro [3].

High impact information on trans-Oxathiolan-C

However, wild-type IC50 values in regard to both (-) and (+) dOTC were obtained when these recombinant viruses were grown in cord blood mononuclear cells (CBMC) [1].
Human immunodeficiency virus type 1 (HIV-1) variants were selected for resistance against the (+) and (-) enantiomers of a novel nucleoside analogue, 2'-deoxy-3'-oxa-4'-thiocytidine (dOTC), using the infectious molecular clone HXB2D grown in the MT-4 line of human T cells [1].
In vitro, SPD754 retained activity against most NRTI-resistant HIV-1 clinical isolates and showed a low propensity to cause myelotoxicity and mitochondrial toxicity [4].
SPD754 had no significant effects on cell viability or mitochondrial DNA in HepG2 or MT-4 cells during 28-day exposure at concentrations up to 200 microM [4].
SPD754 showed a low potential for myelotoxicity against human bone marrow [4].

Chemical compound and disease context of trans-Oxathiolan-C

Antiviral activity of 2'-deoxy-3'-oxa-4'-thiocytidine (BCH-10652) against lamivudine-resistant human immunodeficiency virus type 1 in SCID-hu Thy/Liv mice [5].
The patterns of resistance-conferring mutations that are selected in HIV-1 reverse transcriptase (RT) by the racemates of 2'-dideoxy-3'-oxa-4'-thiocytidine (+/-)dOTC and its fluorinated derivative (+/-)dOTFC were characterized [6].
Both the enantiomers (-)dOTC (BCH-10618) and (+)dOTC (BCH-10619) had equivalent activity against wild-type strains of HIV-1 in C8166 T-cells (EC50 1.0-10.0 microM) and in PBMCs (EC50 0.1-3.0 microM) [7].

Biological context of trans-Oxathiolan-C

There was no significant effect of dose size on the pharmacokinetics of racemic dOTC [8].
0. The mean absolute bioavailabilities of (+) and (-) dOTC were 77.2% (coefficient of variation [given as a percentage] [CV%], 14) and 80.7% (CV%, 15), respectively [9].
In tissue culture studies, the 50% toxicity levels for dOTC, which were determined by using [(3)H]thymidine uptake as a measure of logarithmic-phase cell proliferation, was greater than 100 microM for all cell lines tested [10].
Neither AUC (p > or = 0.10) nor Cmax (p > or = 0.35) differed significantly between the fed and fasted study periods for either (-) or (+) dOTC [11].
Drug resistance and drug combination features of the human immunodeficiency virus inhibitor, BCH-10652 [(+/-)-2'-deoxy-3'-oxa-4'-thiocytidine, dOTC] [7].

Anatomical context of trans-Oxathiolan-C

When administered orally to rats, dOTC was well absorbed, with a bioavailability of approximately 77%, with a high proportion (approximately 16.5% of the levels in serum) found in the cerebrospinal fluid [10].

Associations of trans-Oxathiolan-C with other chemical compounds

The mean 50% inhibitory concentration of dOTC for drug-naive isolates was 1.76 microM, rising to only 2.53 and 2.5 microM for viruses resistant to 3TC and viruses resistant to 3TC and AZT, respectively [10].
Intracellular metabolism studies showed that dOTC is phosphorylated within cells via the deoxycytidine kinase pathway and that approximately 2 to 5% of dOTC is converted into the racemic triphosphate derivatives, which had measurable half-lives (2 to 3 hours) within cells [10].
In contrast, virus resistant to dOTC and (-)dOTC took longer to appear (15-20 passages), with a methionine (ATG) to valine (GTG) amino acid change at position 184 identified in both cases [7].

Analytical, diagnostic and therapeutic context of trans-Oxathiolan-C

Subjects received single oral doses of 100, 200, 400, 800, and 1,600 mg of racemic dOTC in a placebo-controlled, dose-rising, incomplete crossover study design, and the pharmacokinetics of both (+)dOTC and (-)dOTC were determined [8].

References

Selection and characterization of HIV-1 variants resistant to the (+) and (-) enantiomers of 2'-deoxy-3'-oxa-4'-thiocytidine (dOTC). Richar, N., Quan, Y., Salomon, H., Hsu, M., Bedard, J., Harrigan, P.R., Rando, R., Mansour, T., Bowlin, T.L., Wainberg, M.A. Antivir. Ther. (Lond.) (1999) [Pubmed]
Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretroviral-naive, HIV-infected patients. Cahn, P., Cassetti, I., Wood, R., Phanuphak, P., Shiveley, L., Bethell, R.C., Sawyer, J. AIDS (2006) [Pubmed]
Anti-human immunodeficiency virus and anti-hepatitis-B virus activities and toxicities of the enantiomers of 2'-deoxy-3'-oxa-4'-thiocytidine and their 5-fluoro analogues in vitro. Mansour, T.S., Jin, H., Wang, W., Hooker, E.U., Ashman, C., Cammack, N., Salomon, H., Belmonte, A.R., Wainberg, M.A. J. Med. Chem. (1995) [Pubmed]
In vitro antiretroviral activity and in vitro toxicity profile of SPD754, a new deoxycytidine nucleoside reverse transcriptase inhibitor for treatment of human immunodeficiency virus infection. Gu, Z., Allard, B., de Muys, J.M., Lippens, J., Rando, R.F., Nguyen-Ba, N., Ren, C., McKenna, P., Taylor, D.L., Bethell, R.C. Antimicrob. Agents Chemother. (2006) [Pubmed]
Antiviral activity of 2'-deoxy-3'-oxa-4'-thiocytidine (BCH-10652) against lamivudine-resistant human immunodeficiency virus type 1 in SCID-hu Thy/Liv mice. Stoddart, C.A., Moreno, M.E., Linquist-Stepps, V.D., Bare, C., Bogan, M.R., Gobbi, A., Buckheit, R.W., Bedard, J., Rando, R.F., McCune, J.M. Antimicrob. Agents Chemother. (2000) [Pubmed]
Selection of resistance-conferring mutations in HIV-1 by the nucleoside reverse transcriptase inhibitors (+/-)dOTC and (+/-)dOTFC. Richard, N., Salomon, H., Oliveira, M., Rando, R., Mansour, T., Gu, Z., Wainberg, M.A. Antivir. Chem. Chemother. (2000) [Pubmed]
Drug resistance and drug combination features of the human immunodeficiency virus inhibitor, BCH-10652 [(+/-)-2'-deoxy-3'-oxa-4'-thiocytidine, dOTC]. Taylor, D.L., Ahmed, P.S., Tyms, A.S., Wood, L.J., Kelly, L.A., Chambers, P., Clarke, J., Bedard, J., Bowlin, T.L., Rando, R.F. Antivir. Chem. Chemother. (2000) [Pubmed]
Safety, tolerability, and pharmacokinetics of single oral doses of BCH-10652 in healthy adult males. Smith, P.F., Forrest, A., Ballow, C.H., Martin, D.E., Proulx, L. Antimicrob. Agents Chemother. (2000) [Pubmed]
Absolute bioavailability and disposition of (-) and (+) 2'-deoxy- 3'-oxa-4'-thiocytidine (dOTC) following single intravenous and oral doses of racemic dOTC in humans. Smith, P.F., Forrest, A., Ballow, C.H., Martin, D.E., Proulx, L. Antimicrob. Agents Chemother. (2000) [Pubmed]
Anti-human immunodeficiency virus type 1 activity, intracellular metabolism, and pharmacokinetic evaluation of 2'-deoxy-3'-oxa-4'-thiocytidine. de Muys, J.M., Gourdeau, H., Nguyen-Ba, N., Taylor, D.L., Ahmed, P.S., Mansour, T., Locas, C., Richard, N., Wainberg, M.A., Rando, R.F. Antimicrob. Agents Chemother. (1999) [Pubmed]
Effect of food on the pharmacokinetics of (-) and (+) dOTC when administered as an oral racemate. Smith, P.F., Forrest, A., Adams, J.M., Ballow, C.H. Journal of clinical pharmacology. (2002) [Pubmed]

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