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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

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

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

Pattern recognition methods in microarray based oncology study

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Frontiers of Electrical and Electronic Engineering in China 2009年第3期4卷 243-250页

作者： Xuesong LU Xuegong ZHANG merck sharp&dohme(China)Ltd. Shanghai OfficeShanghai 200040China Bioinformatics Division TNLIST/Department of AutomationTsinghua UniversityBeijing 100084China

With the development of microarray technology,more and more microarray-based oncology studies have been carried *** amounts of data and the complexity of cancer mechanisms make data analysis methods a much more important part of these *** this article,we will mainly focus on the pattern recognition methods used in oncology *** to the availability of sample information,the unsupervised methods and supervised methods are reviewed ***,some possible future directions are proposed.

关键词： pattern recognition methods microarray oncology

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)

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

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 *** diameter and the Zeta potential were *** HBV-specific 10-23DRzs were designed according to the sequences of S and C genes of *** 10-23DRzs were connected to FSNPs,which constituted 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 *** combination of DNA and FSNPs effectively protected DNA from nuclease *** of FSNPs-DNA significantly inhibited the expression of HBV S and C genes compared to the liposome control *** 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 *** VCR-loaded PEG-PLGA-NPs were prepared by the double emulsion solvent evaporation *** main experimental factors,which influenced the physical and chemical properties of the nanoparticles,were investigated and *** Under optimal conditions,the VCR-loaded PEG-PLGA-NPs had an average diameter of 135.9 nm with narrow size *** 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 *** 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

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山药新木脂素成分的研究

药学学报 1986年第5期21卷 361-365页

作者：韩桂秋,李书明,李长龄,J P Springer,S B Hwang,M N Chang 北京医科大学药学院北京医科大学药学院北京医科大学药学院 merck sharp & dohme Research Lab. USA merck sharp & dohme Research Lab. USA merck sharp & dohme Research Lab. USA

自胡椒科(Piperaceae)植物山蒟(Piper hancei Maxim)的藤茎分离到三种木脂素类化合物,根据光谱(UV,IR,NMR和MS)及X-射线单晶衍射分析,化合物Ⅲ确定为新结构,(7S,8R,3′S)-1′-烯丙基-3′-甲氧基-7-(3,4-次甲二氧基苯基)-7,8,3′,6′-四... 详细信息

自胡椒科(Piperaceae)植物山蒟(Piper hancei Maxim)的藤茎分离到三种木脂素类化合物,根据光谱(UV,IR,NMR和MS)及X-射线单晶衍射分析,化合物Ⅲ确定为新结构,(7S,8R,3′S)-1′-烯丙基-3′-甲氧基-7-(3,4-次甲二氧基苯基)-7,8,3′,6′-四氢-6′-氧苯并呋喃,命名为山蒟素(hancinone);化合物Ⅰ为海风藤酮(kadsurenone);化合物Ⅱ为denudatin B。后两种化合物首次从本植物中分离。山蒟民间草药,治疗风湿和关节炎。以血小板活化因子(PAF)受体结合实验及PAF血小板聚集实验测定,化合物Ⅰ的抑制作用最强,化合物Ⅱ明显减弱,而化合物Ⅲ无活性

关键词：新木脂素山药素海风藤酮 denudatin B 山蒟血小板活化因子