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. 1994 Oct;38(10):2387–2391. doi: 10.1128/aac.38.10.2387

1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl] cytosine, an intracellular prodrug for (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine with improved therapeutic index in vivo.

N Bischofberger 1, M J Hitchcock 1, M S Chen 1, D B Barkhimer 1, K C Cundy 1, K M Kent 1, S A Lacy 1, W A Lee 1, Z H Li 1, D B Mendel 1, et al.
PMCID: PMC284749  PMID: 7840575

Abstract

1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosi ne (cyclic [cHPMPC]) was evaluated as a novel antiviral agent in comparison with (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC). Evaluation for in vitro activity against herpes simplex virus type 2 in MA-104 and MRC-5 cells showed that both cHPMPC and HPMPC have comparable activities and cytotoxicities. cHPMPC was found to be stable on incubation in human plasma and human liver homogenates. Intracellular metabolism studies revealed that cHPMPC was converted inside of the cells to HPMPC and then to the monophosphate, the diphosphate, and the monophosphate choline metabolites. In a mouse herpes simplex virus type 2 encephalitis model, both cHPMPC and HPMPC exhibited similar potencies in vivo. Nephrotoxicity, which is the dose-limiting toxicity of HPMPC, was assessed in a 14-day repeated-dose toxicity study in rats; cHPMPC has an improved safety margin of > or = 13-fold over that of HPMPC.

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Selected References

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  1. Chen M. S., Suttmann R. T., Wu J. C., Prisbe E. J. Metabolism of 4'-azidothymidine. A compound with potent and selective activity against the human immunodeficiency virus. J Biol Chem. 1992 Jan 5;267(1):257–260. [PubMed] [Google Scholar]
  2. Connelly M. C., Robbins B. L., Fridland A. Mechanism of uptake of the phosphonate analog (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) in Vero cells. Biochem Pharmacol. 1993 Sep 14;46(6):1053–1057. doi: 10.1016/0006-2952(93)90670-r. [DOI] [PubMed] [Google Scholar]
  3. Cunningham R. F., Israili Z. H., Dayton P. G. Clinical pharmacokinetics of probenecid. Clin Pharmacokinet. 1981 Mar-Apr;6(2):135–151. doi: 10.2165/00003088-198106020-00004. [DOI] [PubMed] [Google Scholar]
  4. De Clercq E. Broad-spectrum anti-DNA virus and anti-retrovirus activity of phosphonylmethoxyalkylpurines and -pyrimidines. Biochem Pharmacol. 1991 Aug 8;42(5):963–972. doi: 10.1016/0006-2952(91)90276-b. [DOI] [PubMed] [Google Scholar]
  5. Folks T., Benn S., Rabson A., Theodore T., Hoggan M. D., Martin M., Lightfoote M., Sell K. Characterization of a continuous T-cell line susceptible to the cytopathic effects of the acquired immunodeficiency syndrome (AIDS)-associated retrovirus. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4539–4543. doi: 10.1073/pnas.82.13.4539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ho H. T., Woods K. L., Bronson J. J., De Boeck H., Martin J. C., Hitchcock M. J. Intracellular metabolism of the antiherpes agent (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine. Mol Pharmacol. 1992 Jan;41(1):197–202. [PubMed] [Google Scholar]
  7. Holý A., Votruba I., Merta A., Cerný J., Veselý J., Vlach J., Sedivá K., Rosenberg I., Otmar M., Hrebabecký H. Acyclic nucleotide analogues: synthesis, antiviral activity and inhibitory effects on some cellular and virus-encoded enzymes in vitro. Antiviral Res. 1990 Jun;13(6):295–311. doi: 10.1016/0166-3542(90)90014-x. [DOI] [PubMed] [Google Scholar]
  8. Keim G. R., Jr, Poutsiaka J. W., Kirpan J., Keysser C. H. Amphotericin B methyl ester hydrochloride and amphotericin B: comparative acute toxicity. Science. 1973 Feb 9;179(4073):584–585. doi: 10.1126/science.179.4073.584. [DOI] [PubMed] [Google Scholar]
  9. Kinsella J. L., Holohan P. D., Pessah N. I., Ross C. R. Transport of organic ions in renal cortical luminal and antiluminal membrane vesicles. J Pharmacol Exp Ther. 1979 Jun;209(3):443–450. [PubMed] [Google Scholar]
  10. Roehm N. W., Rodgers G. H., Hatfield S. M., Glasebrook A. L. An improved colorimetric assay for cell proliferation and viability utilizing the tetrazolium salt XTT. J Immunol Methods. 1991 Sep 13;142(2):257–265. doi: 10.1016/0022-1759(91)90114-u. [DOI] [PubMed] [Google Scholar]
  11. Snoeck R., Schols D., Andrei G., Neyts J., De Clercq E. Antiviral activity of anti-cytomegalovirus agents (HPMPC, HPMPA) assessed by a flow cytometric method and DNA hybridization technique. Antiviral Res. 1991 Jul;16(1):1–9. doi: 10.1016/0166-3542(91)90053-t. [DOI] [PubMed] [Google Scholar]
  12. Tune B. M. Effect of organic acid transport inhibitors on renal cortical uptake and proximal tubular toxicity of cephaloridine. J Pharmacol Exp Ther. 1972 May;181(2):250–256. [PubMed] [Google Scholar]

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