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Discovery of a series of dimethoxybenzene FGFR inhibitors with 5H-pyrrolo[2,3-b]pyrazine scaffold: structure–activity relationship, crystal structural characterization and in vivo study

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Acta Pharmaceutica Sinica B 2019年第2期9卷 351-368页

作者： Peng Wei Bo Liu Ruifeng Wang Yinglei Gao Lanlan Li Yuchi Ma Zhiwei Qian Yuelei Chen Maosheng Cheng Meiyu Geng jingkang shen Dongmei Zhao Jing Ai Bing Xiong Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education Shenyang Pharmaceutical University Department of Medicinal Chemistry Shanghai Institute of Materia Medica Chinese Academy of Sciences Division of Anti-tumor Pharmacology State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences

Genomic alterations are commonly found in the signaling pathways of fibroblast growth factor receptors(FGFRs). Although there is no selective FGFR inhibitors in market, several promising inhibitors have been investigated in clinical trials, and showed encouraging efficacies in patients. By designing a hybrid between the FGFR-selectivity-enhancing motif dimethoxybenzene group and our previously identified novel scaffold, we discovered a new series of potent FGFR inhibitors, with the best one showing sub-nanomolar enzymatic activity. After several round of optimization and with the solved crystal structure, detailed structure–activity relationship was elaborated. Together with in vitro metabolic stability tests and in vivo pharmacokinetic profiling, a representative compound(35) was selected and tested in xenograft mouse model, and the result demonstrated that inhibitor 35 was effective against tumors with FGFR genetic alterations, exhibiting potential for further development.

关键词： Fibroblast growth factor Tyrosine kinase receptor Structure-based Crystallography Selectivity Hybrid 5-Hydrosulfonyl-5Hpyrrolo[2,3-b]pyrazine Inhibitor

Discovery of 4-cyclopropyl-3-(2-((1-cyclopropyl-1H-pyrazol-4-yl) amino) quinazolin-6-yl)-N-(3-(trifluoromethyl) phenyl) benzamides as potent discoidin domain receptor inhibitors for the treatment of idiopathic pulmonary fibrosis

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1943-1962页

作者： Qi Wang Bixi Tang Dandan Sun Ying Dong Yinchun Ji Huanyu Shi Liwei Zhou Yueyue Yang Menglan Luo Qian Tan Lin Chen Yue Dong Cong Li Rongrong Xie Yi Zang jingkang shen Bing Xiong Jia Li Danqi Chen Department of Medicinal Chemistry Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Division of Anti-tumor Pharmacology State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Center for Supramolecular Chemistry and Catalysis and Department of Chemistry College of SciencesShanghai UniversityShanghai 200444China Department of Pharmacology School of PharmacyFudan UniversityShanghai 201203China School of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing 210023China Department of Pulmonary and Critical Care Medicine Shanghai Fifth People’s HospitalFudan UniversityShanghai 200240China Department of Chemistry College of SciencesShanghai UniversityShanghai 200444China School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUCASHangzhou 310024China

Idiopathic pulmonary fibrosis(IPF)is a chronic fatal lung disease with a median survival time of 3–5 *** diagnosis,limited clinical therapy and high mortality together indicate that the development of effective therapeutics for IPF is an urgent *** recent years,it was reported that DDRs are potential targets in anti-fibrosis *** on previous work we carried out further structure modifications and led to a more selective inhibitor 47 by averting some fibrosis-unrelated kinases,such as RET,AXL and *** profiling of compound 47 has demonstrated that it has potent DDR1/2 inhibitory activities,low toxicity,good pharmacokinetic properties and reliable in vivo anti-fibrosis ***,we confirmed that discoidin domain receptors are promising drug targets for IPF,and compound 47 would be a promising candidate for further drug development.

关键词： Idiopathic pulmonary fibrosis Discoidin domain receptor Kinase Inhibitor Docking

Novel indazole-based derivatives as PI3K/mTOR dual inhibitors

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Novel indazole-based derivatives as PI3K/mTOR dual inhibitor...

2012长三角药物化学研讨会

作者： Huayong Zhou Yi Wang Lanping Ma Xin Wang Lin Chen Yi Chen Jian Ding Tao Meng Linhua Meng jingkang shen State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of Sciences

Phosphoinositide-3-kinase(PI3K) has attracted vast attention as a promising target for cancer therapeutics because the deregulation of the PI3K/Akt/mTOR signaling pathway is frequently observed in a wide variety of human cancers.A series of indazole-based derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor ***147 has shown good physical properties and PK parameters,low nanomolar potency against PI3Kαand mTOR,and

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组合化学

上海化工 2002年第3期27卷 26-29页

作者：刘苏友沈竞康胡定宇中国科学院上海药物所上海200031 湖南工程学院湘潭411101

简单介绍了组合化学的发展、特点及其应用,概述了构建组合化学库的方法,如混合分裂法、位置扫描法、单个化合物平行合成法等。

关键词：组合化学混合分裂法位置扫描法平行合成法特点

SCN9A Epileptic Encephalopathy Mutations Display a Gain-offunction Phenotype and Distinct Sensitivity to Oxcarbazepine

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Neuroscience Bulletin 2020年第1期36卷 11-24页

作者： Shuzhang Zhang Zhiping Zhang Yuan shen Yudan Zhu Kun Du jingkang Guo Yonghua Ji Jie Tao Institute of Biomembrane and Biopharmaceutics Shanghai UniversityShanghai 200444China Central Laboratory and Department of Neurology Putuo HospitalShanghai University of Traditional Chinese MedicineShanghai 200062China Department of Clinical Laboratory Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 202150China Xinhua Translational Institute for Cancer Pain Xinhua Hospital Chongming BranchShanghai 202150China Putuo Clinical Medical School Anhui Medical UniversityShanghai 200062China

Genetic mutants of voltage-gated sodium channels(VGSCs)are considered to be responsible for the increasing number of epilepsy *** research has indicated that mutations of one of the VGSC genes,SCN9A(Navl.7),result in febrile seizures and Dravet syndrome in *** these recent efforts,the electrophysiological basis of SCN9A mutations remains ***,we performed a genetic screen of patients with febrile seizures and identified a novel missense mutation of SCN9A(W1150R).Electrophysiological characterization of different SCN9A mutants in HEK293T cells,the previously-reported N641Y and K655R variants,as well as the newly-found W1150R variant,revealed that the current density of the W1150R and N641Y variants was significantly larger than that of the wild-type(WT)*** time constants of recovery from fast inactivation of the N641Y and K655R variants were markedly lower than in the WT *** W1150R variant caused a negative shift of the G-V curve in the voltage dependence of steady-state *** mutants displayed persistent currents larger than the WT *** addition,we found that oxcarbazepine(OXC),one of the antiepileptic drugs targeting VGSCs,caused a significant shift to more negative potential for the activation and inactivation in WT and mutant ***-induced inhibition of currents was weaker in the W1150R variant than in the ***,with administering OXC the time constant of the N641Y variant was longer than those of the other two SCN9A *** all,our results indicated that the point mutation W1150R resulted in a novel gain-of-function *** findings indicated that SCN9A mutants contribute to an increase in seizure,and show distinct sensitivity to OXC.

关键词： Voltage-gated sodium channel SCN9A Epilepsy Electrophysiological function Oxcarbazepine Sensitivity Introduction

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渤海L油田水平井含水变化规律分析

重庆科技学院学报（自然科学版） 2024年第2期26卷 8-13页

作者：赵靖康申春生李媛婷安玉华王鹏飞中海石油天津分公司渤海石油研究院天津300452

渤海L油田现已进入中高含水期,利用水平井挖潜剩余油,部分水平井初期含水较高或者含水上升较快,影响水平井调整挖潜效果。为改变此现象,对L油田多口水平油井的初期含水和含水上升规律加以总结分析,通过“3类6种”曲线反映其规律变化,并... 详细信息

渤海L油田现已进入中高含水期,利用水平井挖潜剩余油,部分水平井初期含水较高或者含水上升较快,影响水平井调整挖潜效果。为改变此现象,对L油田多口水平油井的初期含水和含水上升规律加以总结分析,通过“3类6种”曲线反映其规律变化,并利用数模机理模型进行验证。

关键词：渤海油田水平井剩余油含水含水变化规律人工压裂缝

Discovery of Novel Sulfonamides as Potent and Selective Inhibitors Against Human and Mouse 11 β-Hydroxysteroid Dehydrogenase Type 1

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Discovery of Novel Sulfonamides as Potent and Selective Inhi...

基于渗透率时变的砂岩油藏含水规律表征方法及数模研究

2011年全国药物化学学术会议——药物的源头创新

作者： Guangxin Xia~(a,b),Lin Liu~(a,b),Mengzhu Xue~a,Jianxin Yu~b,Ping Li~b,Haiyan Liu~b,Qian Chen~b,Bing Xiong~(a,*), jingkang shen~(a,b) a State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,555 Zuchongzhi Road,Zhangjiang Hi-Tech Park,Shanghai 201203,China b Central Research Institute,Shanghai Pharmaceutical Holding Co.,Ltd.,898 Ha Lei Road, Zhangjiang Hi-Tech Park,Shanghai 201203,China

＜正＞Several classes of non-steroid 11β-HSD1 inhibitors have been developed as promising treatments for Type 2 Diabetes（T2D）.Using a human 11β-HSD1 selective inhibitor as a starting point,we designed and synthesized a new class of derivatives of 1-arylsulfonyl *** was found that the large lipophilic group on the amino part may lead to cross-species potency towards human and mouse,which will benefit the drug development by evaluating the compounds on rodent *** exploring the structure-activity-relationship,（R）-（+）-Bornylamine derivative is identified as the most potent inhibitor against mouse enzyme 11β-HSD1 with IC50 of 18 *** docking studies revealed the possible different interaction modes of S-enantiomer and R-enantiomer bound to h11β-HSD1 and explained the reason that S-enantiomer is more active than its ***,two potent and isoform-selective compounds, （+）-isopinocampheylamine derivative 8m and（R）-（+）-Bornylamine derivative 81,with suitable in vitro properties,are selected for future PK/PD evaluation on rodent *** study not only provides some compounds as novel h11β-HSD1,but also presents the structure-activity-relationship about designing human/mouse potent 11β-HSD1 inhibitors suitable for in vivo evaluation on rodent model.

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复杂油气藏 2024年第2期17卷 201-207页

作者：赵靖康侯亚伟申春生刘超韩建斌中海石油(中国)有限公司天津分公司渤海石油研究院天津300452

P油田是渤海最大的陆相多层砂岩油藏,历经十多年的注水开发,油田进入中高含水期,由于储层粉砂岩和泥质含量较高且差异较大,层内、层间、平面三大开发矛盾突出,常规数模单井含水上升规律拟合难度大,对油藏数值模拟拟合与开发指标预测有... 详细信息

P油田是渤海最大的陆相多层砂岩油藏,历经十多年的注水开发,油田进入中高含水期,由于储层粉砂岩和泥质含量较高且差异较大,层内、层间、平面三大开发矛盾突出,常规数模单井含水上升规律拟合难度大,对油藏数值模拟拟合与开发指标预测有很大影响。基于油田储层微观结构分析,长期水驱储层微观孔隙结构变化实验研究、现场调整井储层水淹物性变化规律统计分析,结合本油田测井解释孔隙度、渗透率方法,以及水驱油实验、水淹层物性变化规律,建立不同类型储层水驱倍数与渗透率变化比值的关系公式,利用PetrelRE平台和Intersect模拟器实现了注水开发过程局部储层渗透率变大或变小过程,大幅度改善了单井含水上升过程的拟合。

关键词：储层类型注水倍数数值模拟渗透率时变

海上多层砂岩油藏油井压裂充填时机研究与实践——以渤海L油田为例

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石油地质与工程 2024年第5期38卷 70-74页

作者：李媛婷赵靖康侯亚伟申春生肖波中海石油(中国)有限公司天津分公司渤海石油研究院天津300459

渤海多层砂岩油藏L油田目前已进入中高含水期,调整油井压裂充填后的含水率差异较大,部分油井含水率高、日产油达不到设计要求,对油田调整井的部署影响较大。利用多层数模机理,在不同含水时期分别对油井全井各层压裂充填、仅对主力层压... 详细信息

渤海多层砂岩油藏L油田目前已进入中高含水期,调整油井压裂充填后的含水率差异较大,部分油井含水率高、日产油达不到设计要求,对油田调整井的部署影响较大。利用多层数模机理,在不同含水时期分别对油井全井各层压裂充填、仅对主力层压裂充填以及仅对非主力层压裂充填3种压裂充填方式进行效果分析,研究表明,当主力层强水淹厚度达到一定比例时,对主力层压裂充填会导致水窜严重,影响产油量,而对非主力层进行压裂充填,有利于控制油井含水率和增加产油量,为油田调整井射孔压裂充填开发提供依据。

关键词：主力层非主力层压裂充填含水率