扩大3-氟-2-（膦酰基甲氧基）丙基非环状核苷磷酸酯的抗病毒

StephenW

Med Chem. 2017 Jul 6. doi: 10.1021/acs.jmedchem.7b00416. [Epub ahead of print]
Expanding the Antiviral Spectrum of 3-Fluoro-2-(phosphonomethoxy)propyl Acyclic Nucleoside Phosphonates: Diamyl Aspartate Amidate Prodrugs.Luo M1, Groaz E1, Andrei G2, Snoeck R2, Kalkeri R3, Ptak RG3, Hartman T4, Buckheit RW Jr4, Schols D2, De Jonghe S1, Herdewijn P1.
Author information
1Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven , Herestraat 49, 3000 Leuven, Belgium.2Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven , Herestraat 49 bus 1043, 3000 Leuven, Belgium.3Department of Infectious Disease Research, Southern Research Institute , 431 Aviation Way, Frederick, Maryland 21701, United States.4Anti-Infective Research, ImQuest BioSciences , Frederick, Maryland 21704, United States.

AbstractAcyclic 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.


PMID:28682067DOI:10.1021/acs.jmedchem.7b00416

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StephenW

医学化学2017年7月6日。doi：10.1021 / acs.jmedchem.7b00416。 [提前印刷]
扩大3-氟-2-（膦酰基甲氧基）丙基非环状核苷磷酸酯的抗病毒谱：天冬氨酸天冬氨酸酯前体药物。
Luo M1，Groaz E1，Andrei G2，Snoeck R2，Kalkeri R3，Ptak RG3，Hartman T4，Buckheit RW Jr4，Schols D2，De Jonghe S1，Herdewijn P1。
作者信息

1
    药物化学，Rega医学研究所，卢布恩，Herestraat 49，3000 Leuven，比利时。
2
    瑞士Regu医学研究所病毒学与化疗实验室，鲁汶大学，Herestraat 49巴士1043，比利时鲁汶。
3
    Department of Infectious Disease Research，Southern Research Institute，431 Aviation Way，Frederick，Maryland 21701，United States。
4
    Anti-Infective Research，ImQuest BioSciences，Frederick，Maryland 21704，United States。

抽象

已知含有3-氟-2-（膦甲氧基）丙基（FPMP）侧链的非环核苷是适度有效的抗人免疫缺陷病毒（HIV）试剂，而对于广泛的DNA病毒完全没有抗病毒活性。天冬氨酸二酰氨基苯甲酸酯基团的FPMP的膦酸官能度的衍生导致新一代的化合物，其不仅显示出显着改善的抗逆转录病毒效能，而且其特征还在于还涵盖乙型肝炎和疱疹病毒的活性谱。最好的化合物（S）-FPMPA酰胺基前体药物在低浓度的TZM-bl和外周血单核细胞中发挥抗HIV-1的活性，对乙型肝炎病毒（HBV）和水痘带状疱疹病毒VZV）。该前药在酸性和人类血浆培养基中是稳定的，但是其在半衰期为2分钟的人肝微粒体中有效地加工。 （R）异构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，含有嘧啶的前体药物（S）-Asp-FPMPC是该系列中唯一一个证明微摩尔人巨细胞病毒（HCMV）效力的同系物。

结论：
    28682067
DOI：
    10.1021 / acs.jmedchem.7b00416