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Expanding the Antiviral Spectrum of 3-Fluoro-2-(phosphonomethoxy)propyl Acyclic Nucleoside Phosphonates: Diamyl Aspartate Amidate Prodrugs
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-07-06 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00416 Min Luo 1 , Elisabetta Groaz 1 , Graciela Andrei 2 , Robert Snoeck 2 , Raj Kalkeri 3 , Roger G. Ptak 3 , Tracy Hartman 4 , Robert W. Buckheit 4 , Dominique Schols 2 , Steven De Jonghe 1 , Piet Herdewijn 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-07-06 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00416 Min Luo 1 , Elisabetta Groaz 1 , Graciela Andrei 2 , Robert Snoeck 2 , Raj Kalkeri 3 , Roger G. Ptak 3 , Tracy Hartman 4 , Robert W. Buckheit 4 , Dominique Schols 2 , Steven De Jonghe 1 , Piet Herdewijn 1
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Acyclic nucleosides containing a 3-fluoro-2-(phosphonomethoxy)propyl (FPMP) side chain are known to be moderately potent antihuman immunodeficiency virus (HIV) agents, while being completely devoid of antiviral activity against a wide range of DNA viruses. The derivatization of the phosphonic acid functionality of FPMPs with a diamyl aspartate phenoxyamidate group led to a novel generation of compounds that not only demonstrate drastically improved antiretroviral potency but also are characterized by an expanded spectrum of activity that also covers hepatitis B and herpes viruses. The best compound, the (S)-FPMPA amidate prodrug, exerts anti-HIV-1 activity in TZM-bl and peripheral blood mononuclear cells at low nanomolar concentrations and displays excellent potency against hepatitis B virus (HBV) and varicella-zoster virus (VZV). This prodrug is stable in acid and human plasma media, but it is efficiently processed in human liver microsomes with a half-life of 2 min. The (R) isomeric guanine derivative emerged as a selectively active anti-HIV and anti-HBV inhibitor, while being nontoxic to human hepatoblastoma cells. Notably, the pyrimidine containing prodrug (S)-Asp-FPMPC is the only congener within this series to demonstrate micromolar antihuman cytomegalovirus (HCMV) potency.
中文翻译：
扩大3-氟-2-（膦酰基甲氧基）丙基无环核苷膦酸酯的抗病毒谱：天门冬氨酸二酰胺A酸酯前药
已知含有3-氟-2-（膦酰基甲氧基）丙基（FPMP）侧链的无环核苷是中等效力的抗人免疫缺陷病毒（HIV）剂，而完全没有针对多种DNA病毒的抗病毒活性。FPMPs的膦酸官能团与天冬氨酸二戊基苯氧酰胺酯基团的衍生化产生了新一代的化合物，这些化合物不仅显示出极大的抗逆转录病毒效力，而且其活性范围广，还涵盖了乙型肝炎和疱疹病毒。最好的化合物，（S-FPMPA酰胺化物前药在低纳摩尔浓度下在TZM-b1和外周血单核细胞中发挥抗HIV-1活性，对乙型肝炎病毒（HBV）和水痘带状疱疹病毒（VZV）表现出出色的效力。该前药在酸性和人血浆介质中稳定，但在人肝微粒体中有效处理，半衰期为2分钟。（R）异构体鸟嘌呤衍生物作为选择性活性的抗HIV和抗HBV抑制剂出现，同时对人肝母细胞瘤细胞无毒。值得注意的是，含嘧啶的前药（S）-Asp-FPMPC是该系列中唯一显示微摩尔抗人巨细胞病毒（HCMV）效力的同类物。
更新日期：2017-07-06
中文翻译：
扩大3-氟-2-（膦酰基甲氧基）丙基无环核苷膦酸酯的抗病毒谱：天门冬氨酸二酰胺A酸酯前药
已知含有3-氟-2-（膦酰基甲氧基）丙基（FPMP）侧链的无环核苷是中等效力的抗人免疫缺陷病毒（HIV）剂，而完全没有针对多种DNA病毒的抗病毒活性。FPMPs的膦酸官能团与天冬氨酸二戊基苯氧酰胺酯基团的衍生化产生了新一代的化合物，这些化合物不仅显示出极大的抗逆转录病毒效力，而且其活性范围广，还涵盖了乙型肝炎和疱疹病毒。最好的化合物，（S-FPMPA酰胺化物前药在低纳摩尔浓度下在TZM-b1和外周血单核细胞中发挥抗HIV-1活性，对乙型肝炎病毒（HBV）和水痘带状疱疹病毒（VZV）表现出出色的效力。该前药在酸性和人血浆介质中稳定，但在人肝微粒体中有效处理，半衰期为2分钟。（R）异构体鸟嘌呤衍生物作为选择性活性的抗HIV和抗HBV抑制剂出现，同时对人肝母细胞瘤细胞无毒。值得注意的是，含嘧啶的前药（S）-Asp-FPMPC是该系列中唯一显示微摩尔抗人巨细胞病毒（HCMV）效力的同类物。
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