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

被引：87

作者：

BISCHOFBERGER, N ^{[1
]}

HITCHCOCK, MJM ^{[1
]}

CHEN, MS ^{[1
]}

BARKHIMER, DB ^{[1
]}

CUNDY, KC ^{[1
]}

KENT, KM ^{[1
]}

LACY, SA ^{[1
]}

LEE, WA ^{[1
]}

LI, ZH ^{[1
]}

MENDEL, DB ^{[1
]}

SMEE, DF ^{[1
]}

SMITH, JL ^{[1
]}

机构：

[1] UTAH STATE UNIV,LOGAN,UT 84322

来源：

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY | 1994年 / 38卷 / 10期

关键词：

D O I：

10.1128/AAC.38.10.2387

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

1-[((S)-2-Hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine (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 greater than or equal to 13-fold over that of HPMPC.

引用

页码：2387 / 2391

页数：5

共 20 条

[1]

CHEN MS, 1992, J BIOL CHEM, V267, P257

[2] METABOLISM OF 1-(S)-(3-HYDROXY-2-PHOSPHONOMETHOXYPROPYL)-CYTOSINE (HPMPC) IN HUMAN EMBRYONIC LUNG-CELLS [J].