Potent anti-murine cytomegalovirus activity and reduced nephrotoxicity of ganciclovir cyclic phosphonate.
Potent anti-murine cytomegalovirus activity and reduced nephrotoxicity of ganciclovir cyclic phosphonate.
复制标题
更昔洛韦环磷酸盐具有有效的抗鼠巨细胞病毒活性并降低肾毒性。
DOI：
10.1128/aac.40.8.1964
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Reist,EJ
中科院分区：
文献类型：
--
作者：
Smee,DF;Reist,EJ
更昔洛韦环膦酸酯（SR 3775）是更昔洛韦膦酸酯（9-[（（+/-）-1-羟甲基-3-膦酰基）丙氧基甲基]鸟嘌呤）的R对映异构体（SR 3773）的衍生物，两者均为人巨细胞病毒和鼠巨细胞病毒（MCMV）的强效抑制剂。针对MCMV的野生型和4种耐药株，SR 3773的效力是SR 3775的2.3至3倍。在重度联合免疫缺陷小鼠中，SR 3775对MCMV感染的活性约为SR 3773的一半。然而，在50 mg/kg体重/天剂量下，SR 3773导致20 - 30%的肾小管破坏（但在25 mg/kg/天剂量下未产生毒性），而在600 mg/kg/天剂量下，SR 3775在14天内未显示出有害的肾脏作用。SR 3775在小鼠中的治疗指数至少是SR 3773的12倍，使其成为治疗人巨细胞病毒疾病的候选药物。
Ganciclovir cyclic phosphonate (SR3775) is a derivative of the R enantiomer (SR3773) of ganciclovir phosphonate (9-[((+/-)-1-hydroxymethyl-3-phosphono)propyloxymethyl]guanine), both of which are potent inhibitors of human ctyomegalovirus and murine cytomegalovirus (MCMV). Against wild-type and four drug-resistant strains of MCMV, SR3773 was 2.3- to 3-fold more potent than SR3775. SR3775 was about half as active as SR3773 against MCMV infections in severe combined immunodeficient mice. However, whereas SR3773 caused 20 to 30% destruction of renal tubules at 50 mg/kg of body weight per day (but exerted no toxicity at 25 mg/kg/day), SR3775 showed no deleterious renal effects at 600 mg/kg/day over 14 days. SR3775 has a therapeutic index at least 12 times higher than SR3773 in mice, making it a candidate for the treatment of human cytomegalovirus disease.