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The Discovery and Development of Boceprevir:A Novel, First-generation Inhibitor of the Hepatitis C Virus NS3/4A Serine Protease

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Journal of Clinical and Translational Hepatology 2013年第1期1卷 22-32页

作者： Anita Y. M. Howe Srikanth Venkatraman merck sharp & dohme Corp. Whitehouse Station NJ USA

An estimated 2–3%of the world's population is infected with hepatitis C virus (HCV), making it a major global health problem. Consequently, over the past 15 years, there has been a concerted effort to understand the pathophysiology of HCV infection and the molecular virology of replication, and to utilize this knowledge for the development of more effective treatments. The virally encoded non-structural serine pro-tease (NS3) is required to process the HCV polyprotein and release the individual proteins that form the viral RNA replication machinery. Given its critical role in the replication of HCV, the NS3 protease has been recognized as a potential drug target for the development of selective HCV therapies. In this review, we describe the key scientific discoveries that led to the approval of boceprevir, a first-generation, selective, small molecule inhibitor of the NS3 protease. We highlight the early studies that reported the crystal structure of the NS3 protease, its role in the processing of the HCV polyprotein, and the structural requirements critical for substrate clea-vage. We also consider the novel attributes of the NS3 protease-binding pocket that challenged development of small molecule inhibitors, and the studies that ultimately yielded milligram quantities of this enzyme in a soluble, tractable form suitable for inhibitor screening programs. Finally, we describe the discovery of boceprevir, from the early chemistry studies, through the development of high-throughput assays, to the phase Ⅲ clinical development program that ultimately provided the basis for approval of this drug. This latest phase in the development of boceprevir represents the culmination of a major global effort to under-stand the pathophysiology of HCV and develop small mole-cule inhibitors for the NS3 protease.

关键词： Biochemistry Synthesis Sustained virologic response

Validation of Automated Dilution and Transfer Methods for Rapid Assessment of Functional Immune Responses to Meningococcal Vaccines

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World Journal of Vaccines 2013年第3期3卷 98-101页

作者： Angela M. Payne Xu Liu Michael J. Caulfield Jon H. Heinrichs Vaccines Basic Research Merck Sharp and Dohme Corp. West Point USA Vaccines Basic Research Merck Sharp and Dohme Corp. West Point USA.

A high-throughput Serum Bactericidal Assay (SBA) was developed to monitor the functional antibody responses to capsular polysaccharide antigens from multiple serotypes of Neisseria meningitidis. This assay measures the ability of an antibody, aided by complement, to mediate killing of bacteria. Functional assays of this type are increasingly used in the quality control arena as potency release tests. Consequently, there has been an enhanced requirement for reproducibility in the performance of this type of assay. Assay validation is, therefore, important to facilitate understanding of the significance of values obtained, and to enable appropriate and informed use of the assay. This study involved the evaluation of the high-throughput serum bactericidal assay including the effects of different dilution and transfer techniques on assay performance. The results presented here demonstrate the repeatability, and the precision and ruggedness of the assay.

关键词： Serum Bactericidal Assay SBA Neisseria meningitides Automation Repeatability

Effects of particle size on the triboelectrification phenomenon in pharmaceutical excipients:Experiments and multi-scale modeling

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Asian Journal of Pharmaceutical Sciences 2016年第5期11卷 603-617页

作者： Raj Mukherjee Vipul Gupta Shivangi Naik Saurabh Sarkar Vinit Sharma Prasad Peri Bodhisattwa Chaudhuri Department of Pharmaceutical Sciences University of ConnecticutStorrsCT 06269USA Institute of Material Sciences University of ConnecticutStorrsCT 06269USA Merck Sharp and Dohme West PointPA 19486USA

Particle sizes play a major role to mediate charge transfer, both between identical and different material surfaces. The study probes into the probable mechanism that actuates opposite polarities between two different size fractions of the same material by analyzing the charge transfer patterns of two different sizes of microcrystalline cellulose(MCC). Quantum scale calculations confirmed alteration of charge transfer capacities due to variation of moisture content predicted by multiple surface and bulk analytical techniques. Discrete Element Method(DEM) based multi-scale computational models pertinent to predict charge transfer capacities were further implemented, and the results were in accordance to the experimental charge profiles.

关键词： Tribocharging Work function Excipient Discrete Element Modeling

10-23DRzs mediated by fluorescent silica nanoparticles inhibit expression of HBV

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中国现代医学杂志 2011年第3期21卷 354-359页

作者： Shi-neng Yan Hong-yuan Zhu Hui-ying Li Qi-lu Wang Jia-gen Wen Li-qun Kang Jin-feng Zhao Yang-de Zhang National Key Laboratory of Nanobiotechnology Ministry of Health Changsha Hunan 410008 P.R.China merck sharp & dohme Changsha Hunan 410008 P.R.China

Objective To prepare fluorescent silica nanoparticles(FSNPs) carrying 10-23 deoxyribozymes(10-23DRzs) and to evaluate their inhibitory effect on human hepatitis B virus(HBV).Methods The FSNPs were prepared by microemulsion method and further modified by NaCl.Their diameter and the Zeta potential were tested.The HBV-specific 10-23DRzs were designed according to the sequences of S and C genes of HBV.The 10-23DRzs were connected to FSNPs,which constituted the FSNPs-DNA.The connecting efficiency and the protective effect of nanoparticles on 10-23DRzs were tested by sodium dodecyl sulfate polyacrylamide gel electrophoresis(SDS-PAGE).The HepG2.2.15 cells were transfected by FSNPs-DNA,of which the inhibitory effects on HBsAg and HBeAg were analyzed by enzyme-linked immunosorbent assay(ELISA).Results The nanoparticles were spherical and uniform in size,with a diameter of 220 nm and the surface Zeta potential of +15.2 mV.The combination of DNA and FSNPs effectively protected DNA from nuclease degradation.Transfection of FSNPs-DNA significantly inhibited the expression of HBV S and C genes compared to the liposome control group.Conclusion The FSNPs have been successfully prepared and efficiently connected to HBV-specific 10-23DRzs,which significantly inhibit the expression of HBV S and C genes in cell culture.

关键词： 10-23DRzs FSNPs HBV gene therapy

Preparation and quality evaluation of vincristine sulfate-loaded PEG-PLGA nanoparticles

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中国现代医学杂志 2011年第6期21卷 727-732页

作者： Ting-ting Guo Hong-yuan Zhu Wei Xie Yan-qin Zhou Ning Wang Kai Qiu Chun-fang Guo Yu-xiang Chen School of Pharmacy Central South University Changsha Hunan 410078 P.R.China merck sharp & dohme Pharmaceuticals Changsha Hunan 410008 P.R.China

Objective To prepare the PEG-PLGA nanoparticles loaded with vincristine sulfate(VCR-loaded PEG-PLGA-NPs) and evaluate their quality.Methods VCR-loaded PEG-PLGA-NPs were prepared by the double emulsion solvent evaporation method.The main experimental factors,which influenced the physical and chemical properties of the nanoparticles,were investigated and optimized.Results Under optimal conditions,the VCR-loaded PEG-PLGA-NPs had an average diameter of 135.9 nm with narrow size distribution.The encapsulation efficiency was 68.2%,while the drug loading capacity was 8.34%.In vitro,VCR was released from the PEG-PLGA-NPs sustainedly for more than 13 days with the total amount of 81%.Moreover,the VCR-loaded PEG-PLGA-NPs were relatively stable,which was confirmed by the stability testing.Conclusion The VCR-loaded PEG-PLGA-NPs are a promising nano drug with controlled release,which can be applied widely.

关键词： PEG-PLGA nanoparticles vincristine sulfate preparation release

狭义相对论的逻辑不自洽问题和新伽利略时空观

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北京石油化工学院学报 2006年第4期14卷 4-16页

作者：马青平 merck sharp & dohme Research Laboratories Harlow CM20 2QRUK

科学理论需要在逻辑上自洽。分析了狭义相对论对高速运动的不稳定微观粒子寿命延长的解释,发现狭义相对论的解释否定了光速不变原理或相对论性时空观。进一步分析发现,在狭义相对论“时间膨胀”和“长度收缩”的推导过程中,观察系和被... 详细信息

科学理论需要在逻辑上自洽。分析了狭义相对论对高速运动的不稳定微观粒子寿命延长的解释,发现狭义相对论的解释否定了光速不变原理或相对论性时空观。进一步分析发现,在狭义相对论“时间膨胀”和“长度收缩”的推导过程中,观察系和被观察系的指定完全相反。这一现象说明“时间膨胀”和“长度收缩”不是狭义相对论的逻辑结果,狭义相对论的逻辑结论应该是“时间收缩”和“长度收缩”(或“时间膨胀”和“长度膨胀”)。在狭义相对论的理论框架内不能正确地推导出运动物体的横质量,在狭义相对论的框架内得出正确横质量公式的推导都存在逻辑或物理错误。因此,狭义相对论在逻辑上是不自洽的,相对论性时空观没有实验证据。现代物理学应该建立在以局部优势引力场为相对优越参照系的新伽利略时空观的基础上。从光传播媒介对应于局部优势引力场这一原则出发,解释了迈克尔逊-莫雷实验、菲索流水光速实验和光行差现象。“运动质量”可由运动物体在受电磁场或引力场作用时受力的大小与该物体的运动速度有关得到解释。不稳定粒子寿命和物理时钟受各自的运动状态影响,也可以分别由粒子衰变和物理时钟依赖的具体物理过程受其相对于局部优势引力场的运动状态的影响来解释。

关键词：时间膨胀长度收缩运动质量洛伦兹变换光行差

Emodin induces apoptosis in human prostate cancer cell LNCaP

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Asian Journal of Andrology 2008年第4期10卷 625-634页

作者： Chun-Xiao Yu Xiao-Qian Zhang Lu-Dong Kang Peng-Ju Zhang Wei-Wen Chen Wen-Wen Liu Qing-Wei Liu Jian-Ye Zhang Department of Biochemistry and Molecular Biology Shandong University School of Medicine Jinan 250012 China merck sharp ＆ dohme Beijing 100738 China Positron Emission Tomography and Computer Tomography （PET-CT） Center Shandong Provincial Hospital Jinan 250021 China

Aim： To elucidate effects and mechanisms of emodin in prostate cancer cells. Methods： Viability of emodin-treated LNCaP cells and PC-3 cells was measured by MTT assay. Following emodin treatments, DNA fragmentation was assayed by agarose gel electrophoresis. Apoptosis rate and the expression of Fas and FasL were assayed by flow cytometric analysis. The mRNA expression levels of androgen receptor （AR）, prostate-specific antigen （PSA）, p53, p21, Bcl-2, Bax, caspase-3, -8, -9 and Fas were detected by RT-PCR, and the protein expression levels of AR, p53 and p21 were detected by Western blot analysis. Results： In contrast to PC-3, emodin caused a marked increase in apoptosis and a decrease in cell proliferation in LNCaP cells. The expression of AR and PSA was decreased and the expression of p53 and p21 was increased as the emodin concentrations were increased. In the same time, emodin induced apoptosis of LNCaP cells through the upregulation of caspase-3 and -9, as well as the increase of Bax/Bcl-2 ratio. However, it did not involve modulation of Fas or caspase-8 protein expression. Conclusion： In prostate cancer cell line, LNCaP, emodin inhibites the proliferation by AR and p53-p21 pathways, and induces apoptosis via the mitochondrial pathway.

关键词： emodin prostate cancer LNCaP PC-3 proliferation androgen receptor p53 apoptosis mitochondrial pathway

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试验性杀虫杀螨剂abamectin

农药译丛 1991年第4期13卷 56-58页

作者：武辉 merck sharp & dohme公司

杀虫杀螨剂abamectin(MK-936)系merck sharp&dohme公司的研究室发现的一种由土壤微生物Streptomyces avermitilis产生的天然物,属新型的大环内酯类。它是两种具生物活性的Avermectin同系物的混合物,其中含≥80％的Avermectin B_(1a)和... 详细信息

杀虫杀螨剂abamectin(MK-936)系merck sharp&dohme公司的研究室发现的一种由土壤微生物Streptomyces avermitilis产生的天然物,属新型的大环内酯类。它是两种具生物活性的Avermectin同系物的混合物,其中含≥80％的Avermectin B_(1a)和≤20％的Avermectin B_(1b)。该药剂能有效地防治众多的。

关键词：杀虫剂杀螨剂大环内酯

Quantitation of Genetox Impurities Using a Surrogate Standard Approach

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Journal of Analytical Sciences, Methods and Instrumentation 2013年第3期3卷 167-172页

作者： Heather Wang Regina Nardi Yuri Bereznitski Roy Helmy David J. Waterhouse Analytical Chemistry Merck Research Laboratories Merck Sharp & Dohme Corp. Rahway USA.

With the ever increasing complexity of active pharmaceutical ingredient (API) preparations, more potential genotoxic impurities (PGI’s) are being observed. It is thus necessary to determine if these PGI’s are present in the final API’s, and if they are present, to ensure the levels are acceptable for any clinical uses. For PGI’s that have authentic standards available, quantitation can be accomplished in a straightforward manner. However, for PGI’s that are expected to form through rearrangements or side reactions, authentic standards may not be readily available, significantly complicating the analysis. In this study we describe a surrogate standard approach for quantifying PGI’s that allows for relative response factor calculations of PGI species utilizing both gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS).

关键词： Potential Genotoxic Impurity (PGI) Active Pharmaceutical Ingredient (API) Mass Spectrometry Surrogate Standard Analyte Relative Response Factor (RRF)