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Prediction of clinical pharmacokinetic parameters of linezolid using animal data by allometric scaling: applicability for the development of novel oxazolidinones.通过异速生长标度法利用动物数据预测利奈唑胺的临床药代动力学参数：对新型恶唑烷酮类药物开发的适用性
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Synthesis of substituted 6-anilinouracils and their inhibition of DNA polymerase IIIC and Gram-positive bacterial growth.取代6-苯胺基尿嘧啶的合成及其对DNA聚合酶IIIC和革兰氏阳性菌生长的抑制作用。
J Med Chem. 2003 Jun 19;46(13):2731-9. doi: 10.1021/jm020591z.
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Novel pyrazolo[3,4-d]pyrimidine-based inhibitors of Staphlococcus aureus DNA polymerase III: design, synthesis, and biological evaluation.新型基于吡唑并[3,4-d]嘧啶的金黄色葡萄球菌DNA聚合酶III抑制剂：设计、合成及生物学评价
J Med Chem. 2003 May 8;46(10):1824-30. doi: 10.1021/jm020483c.
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Low frequencies of resistance among Staphylococcus and Enterococcus species to the bactericidal DNA polymerase inhibitor N(3)-hydroxybutyl 6-(3'-ethyl-4'-methylanilino) uracil.葡萄球菌属和肠球菌属中对杀菌性DNA聚合酶抑制剂N(3)-羟丁基6-(3'-乙基-4'-甲基苯胺基)尿嘧啶耐药的频率较低。
Antimicrob Agents Chemother. 2002 Dec;46(12):3770-5. doi: 10.1128/AAC.46.12.3770-3775.2002.
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Pharmacokinetics, toxicokinetics, distribution, metabolism and excretion of linezolid in mouse, rat and dog.利奈唑胺在小鼠、大鼠和犬体内的药代动力学、毒代动力学、分布、代谢及排泄
Xenobiotica. 2002 Oct;32(10):907-24. doi: 10.1080/00498250210158249.
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PolC-type polymerase III of Streptococcus pyogenes and its use in screening for chemical inhibitors.化脓性链球菌的PolC型聚合酶III及其在化学抑制剂筛选中的应用。
Anal Biochem. 2002 May 1;304(1):110-6. doi: 10.1006/abio.2001.5591.
7
Genetic identification of two distinct DNA polymerases, DnaE and PolC, that are essential for chromosomal DNA replication in Staphylococcus aureus.金黄色葡萄球菌中对染色体DNA复制至关重要的两种不同DNA聚合酶DnaE和PolC的基因鉴定。
Mol Genet Genomics. 2001 Dec;266(4):564-71. doi: 10.1007/s004380100564. Epub 2001 Aug 16.
8
Two essential DNA polymerases at the bacterial replication fork.细菌复制叉处的两种重要DNA聚合酶。
Science. 2001 Nov 23;294(5547):1716-9. doi: 10.1126/science.1066351.
9
Design and synthesis of novel antibacterial agents with inhibitory activity against DNA polymerase III.对DNA聚合酶III具有抑制活性的新型抗菌剂的设计与合成。
Bioorg Med Chem Lett. 2001 Aug 20;11(16):2185-8. doi: 10.1016/s0960-894x(01)00407-3.
10
Pharmacokinetics, metabolism, and excretion of linezolid following an oral dose of [(14)C]linezolid to healthy human subjects.健康受试者口服[(14)C]利奈唑胺后的药代动力学、代谢及排泄情况。
Drug Metab Dispos. 2001 Aug;29(8):1136-45.

革兰氏阳性DNA聚合酶IIIC酶新型抑制剂的生物学特性

Biological characterization of novel inhibitors of the gram-positive DNA polymerase IIIC enzyme.

作者信息

Kuhl Alexander, Svenstrup Niels, Ladel Christoph, Otteneder Michael, Binas Annegret, Schiffer Guido, Brands Michael, Lampe Thomas, Ziegelbauer Karl, Rübsamen-Waigmann Helga, Haebich Dieter, Ehlert Kerstin

机构信息

Bayer HealthCare AG, Pharma Research EU, D-42096 Wuppertal, Germany.

出版信息

Antimicrob Agents Chemother. 2005 Mar;49(3):987-95. doi: 10.1128/AAC.49.3.987-995.2005.

DOI:10.1128/AAC.49.3.987-995.2005
PMID:15728893
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC549236/
Abstract

Novel N-3-alkylated 6-anilinouracils have been identified as potent and selective inhibitors of bacterial DNA polymerase IIIC, the enzyme essential for the replication of chromosomal DNA in gram-positive bacteria. A nonradioactive assay measuring the enzymatic activity of the DNA polymerase IIIC in gram-positive bacteria has been assembled. The 6-anilinouracils described inhibited the polymerase IIIC enzyme at concentrations in the nanomolar range in this assay and displayed good in vitro activity (according to their MICs) against staphylococci, streptococci, and enterococci. The MICs of the most potent derivatives were about 4 microg/ml for this panel of bacteria. The 50% effective dose of the best compound (6-[(3-ethyl-4-methylphenyl)amino]-3-{[1-(isoxazol-5-ylcarbonyl)piperidin-4-yl]methyl}uracil) was 10 mg/kg of body weight after intravenous application in a staphylococcal sepsis model in mice, from which in vivo pharmacokinetic data were also acquired.

摘要

新型N-3-烷基化6-苯胺基尿嘧啶已被确认为细菌DNA聚合酶IIIC的强效和选择性抑制剂，该酶是革兰氏阳性菌中染色体DNA复制所必需的。已组装了一种用于测量革兰氏阳性菌中DNA聚合酶IIIC酶活性的非放射性测定法。在此测定法中，所述的6-苯胺基尿嘧啶在纳摩尔浓度范围内抑制聚合酶IIIC酶，并对葡萄球菌、链球菌和肠球菌显示出良好的体外活性（根据其最低抑菌浓度）。对于这组细菌，最有效衍生物的最低抑菌浓度约为4微克/毫升。在小鼠葡萄球菌败血症模型中静脉给药后，最佳化合物（6-[(3-乙基-4-甲基苯基)氨基]-3-{[1-(异恶唑-5-基羰基)哌啶-4-基]甲基}尿嘧啶）的50%有效剂量为10毫克/千克体重，同时还获得了其体内药代动力学数据。