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Research Article

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, M J Hitchcock, M S Chen, D B Barkhimer, K C Cundy, K M Kent, S A Lacy, W A Lee, Z H Li, D B Mendel
N Bischofberger
Utah State University, Logan.
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M J Hitchcock
Utah State University, Logan.
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M S Chen
Utah State University, Logan.
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D B Barkhimer
Utah State University, Logan.
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K C Cundy
Utah State University, Logan.
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K M Kent
Utah State University, Logan.
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S A Lacy
Utah State University, Logan.
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W A Lee
Utah State University, Logan.
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Z H Li
Utah State University, Logan.
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D B Mendel
Utah State University, Logan.
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DOI: 10.1128/AAC.38.10.2387
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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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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, M J Hitchcock, M S Chen, D B Barkhimer, K C Cundy, K M Kent, S A Lacy, W A Lee, Z H Li, D B Mendel
Antimicrobial Agents and Chemotherapy Oct 1994, 38 (10) 2387-2391; DOI: 10.1128/AAC.38.10.2387

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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.
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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, M J Hitchcock, M S Chen, D B Barkhimer, K C Cundy, K M Kent, S A Lacy, W A Lee, Z H Li, D B Mendel
Antimicrobial Agents and Chemotherapy Oct 1994, 38 (10) 2387-2391; DOI: 10.1128/AAC.38.10.2387
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