Mingwei Zhou
Hoffmann-La Roche
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Publication
Featured researches published by Mingwei Zhou.
Journal of Medicinal Chemistry | 2016
Zongxing Qiu; Xianfeng Lin; Mingwei Zhou; Yongfu Liu; Wei Zhu; Wenming Chen; Weixing Zhang; Lei Guo; Haixia Liu; Guolong Wu; Mengwei Huang; Min Jiang; Zhiheng Xu; Zheng Zhou; Ning Qin; Shuang Ren; Hongxia Qiu; Sheng Zhong; Yuxia Zhang; Yi Zhang; Xiaoyue Wu; Liping Shi; Fang Shen; Yi Mao; Xue Zhou; Wengang Yang; Jim Zhen Wu; Guang Yang; Alexander V. Mayweg; Hong C. Shen
Targeting the capsid protein of hepatitis B virus (HBV) and thus interrupting normal capsid formation have been an attractive approach to block the replication of HBV viruses. We carried out multidimensional structural optimizations based on the heteroaryldihydropyrimidine (HAP) analogue Bay41-4109 (1) and identified a novel series of HBV capsid inhibitors that demonstrated promising cellular selectivity indexes, metabolic stabilities, and in vitro safety profiles. Herein we disclose the design, synthesis, structure-activity relationship (SAR), cocrystal structure in complex with HBV capsid proteins and in vivo pharmacological study of the 4-methyl HAP analogues. In particular, the (2S,4S)-4,4-difluoroproline substituted analogue 34a demonstrated high oral bioavailability and liver exposure and achieved over 2 log viral load reduction in a hydrodynamic injected (HDI) HBV mouse model.
Journal of Medicinal Chemistry | 2012
Jason Christopher Wong; Guozhi Tang; Xihan Wu; Chungen Liang; Zhenshan Zhang; Lei Guo; Zhenghong Peng; Weixing Zhang; Xianfeng Lin; Zhanguo Wang; Jianghua Mei; Junli Chen; Song Pan; Nan Zhang; Yongfu Liu; Mingwei Zhou; Lichun Feng; Weili Zhao; Shijie Li; Chao Zhang; Meifang Zhang; Yiping Rong; Tai-Guang Jin; Xiongwen Zhang; Shuang Ren; Ying Ji; Rong Zhao; Jin She; Yi Ren; Chunping Xu
Herein, we describe the pharmacokinetic optimization of a series of class-selective histone deacetylase (HDAC) inhibitors and the subsequent identification of candidate predictive biomarkers of hepatocellular carcinoma (HCC) tumor response for our clinical lead using patient-derived HCC tumor xenograft models. Through a combination of conformational constraint and scaffold hopping, we lowered the in vivo clearance (CL) and significantly improved the bioavailability (F) and exposure (AUC) of our HDAC inhibitors while maintaining selectivity toward the class I HDAC family with particular potency against HDAC1, resulting in clinical lead 5 (HDAC1 IC₅₀ = 60 nM, mouse CL = 39 mL/min/kg, mouse F = 100%, mouse AUC after single oral dose at 10 mg/kg = 6316 h·ng/mL). We then evaluated 5 in a biomarker discovery pilot study using patient-derived tumor xenograft models, wherein two out of the three models responded to treatment. By comparing tumor response status to compound tumor exposure, induction of acetylated histone H3, candidate gene expression changes, and promoter DNA methylation status from all three models at various time points, we identified preliminary candidate response prediction biomarkers that warrant further validation in a larger cohort of patient-derived tumor models and through confirmatory functional studies.
RSC Advances | 2017
Mingwei Zhou; Ke En; Yimin Hu; Yufang Xu; Hong C. Shen; Xuhong Qian
The first use of zinc triflate for the cyclopropanation of unprotected oxindoles with vinyl diphenyl sulfonium triflate salt is reported. The reaction proceeded under ambient conditions and consistently provided high yields with broad functional group tolerability. The utility for the late-stage functionalization (LSF) of complex molecules is demonstrated.
Journal of Medicinal Chemistry | 2017
Zongxing Qiu; Xianfeng Lin; Weixing Zhang; Mingwei Zhou; Lei Guo; Buelent Kocer; Guolong Wu; Zhisen Zhang; Haixia Liu; Houguang Shi; Buyu Kou; Taishan Hu; Yimin Hu; Mengwei Huang; S. Frank Yan; Zhiheng Xu; Zheng Zhou; Ning Qin; Yue Fen Wang; Shuang Ren; Hongxia Qiu; Yuxia Zhang; Yi Zhang; Xiaoyue Wu; Kai Sun; Sheng Zhong; Jianxun Xie; Giorgio Ottaviani; Yuan Zhou; Lina Zhu
Described herein are the discovery and structure-activity relationship (SAR) studies of the third-generation 4-H heteroaryldihydropyrimidines (4-H HAPs) featuring the introduction of a C6 carboxyl group as novel HBV capsid inhibitors. This new series of 4-H HAPs showed improved anti-HBV activity and better drug-like properties compared to the first- and second-generation 4-H HAPs. X-ray crystallographic study of analogue 12 (HAP_R01) with Cp149 Y132A mutant hexamer clearly elucidated the role of C6 carboxyl group played for the increased binding affinity, which formed strong hydrogen bonding interactions with capsid protein and coordinated waters. The representative analogue 10 (HAP_R10) was extensively characterized in vitro (ADMET) and in vivo (mouse PK and PD) and subsequently selected for further development as oral anti-HBV infection agent.
Journal of Organic Chemistry | 2018
Mingwei Zhou; Xuefei Tan; Yimin Hu; Hong C. Shen; Xuhong Qian
An efficient chemo- and regioselective N-vinylation of N-heteroarenes has been developed using vinylsulfonium salts. The reaction proceeded under mild and transition-metal-free conditions and consistently provided moderate to high yields of vinylation products with 100% E-stereoselectivity. This reaction is also highly chemoselective, and compatible with a variety of functional groups, such as -NHR, -NH2, -OH, -COOH, ester, etc.
Archive | 2014
Lei Guo; Taishan Hu; Yimin Hu; Buelent Kocer; Xianfeng Lin; Haixia Liu; Alexander V. Mayweg; Zongxing Qiu; Hong Shen; Guozhi Tang; Lisha Wang; Guolong Wu; Shixiang Yan; Weixing Zhang; Mingwei Zhou; Wei Zhu
Archive | 2012
Johannes Aebi; Kurt Amrein; Benoit Hornsperger; Henner Knust; Bernd Kuhn; Yongfu Liu; Hans P. Maerki; Alexander V. Mayweg; Peter Mohr; Xuefei Tan; Mingwei Zhou
Archive | 2012
Johannes Aebi; Kurt Amrein; Wenming Chen; Benoit Hornsperger; Bernd Kuhn; Yongfu Liu; Hans P. Maerki; Alexander V. Mayweg; Peter Mohr; Xuefei Tan; Zhanguo Wang; Mingwei Zhou
Archive | 2012
Johannes Aebi; Kurt Amrein; Serena Fantasia; Benoit Hornsperger; Bernd Kuhn; Yongfu Liu; Hans P. Maerki; Alexander V. Mayweg; Peter Mohr; Michelangelo Scalone; Xuefei Tan; Mingwei Zhou
Archive | 2012
Lichun Feng; Mengwei Huang; Yongfu Liu; Guolong Wu; Shixiang Yan; Hongying Yun; Mingwei Zhou