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Discovery of novel diarylamides as orally active diuretics targeting urea transporters

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Acta Pharmaceutica Sinica B 2021年第1期11卷 181-202页

作者： Shun Zhang Yan Zhao Shuyuan Wang Min li Yue Xu Jianhua Ran Xiaoqiang Geng Jinzhao He Jia Meng Guangying Shao Hong Zhou Zemei Ge Guangping Chen runtao li Baoxue Yang Department of Pharmacology School of Basic Medical SciencesPeking UniversityBeijing 100191China State Key Laboratory of Natural and Biomimetic Drugs Peking UniversityBeijing 100191China Key Laboratory of Molecular Cardiovascular Sciences Ministry of EducationBeijing 100191China School of Pharmaceutical Sciences Peking UniversityBeijing 100191China College of Pharmacy Inner Mongolia Medical UniversityHohhot 010110China Department of Anatomy and Neuroscience Center Chongqing Medical UniversityChongqing 400016China Department of Physiology Emory University School of MedicineAtlantaGA 30322USA

Urea transporters(UT)play a vital role in the mechanism of urine concentration and are recognized as novel targets for the development of salt-sparing ***,UT inhibitors are promising for development as novel *** the present study,a novel UT inhibitor with a diarylamide scaffold was discovered by high-throughput *** of the inhibitor led to the identifi-cation of a promising preclinical candidate,N-[4-(acetylamino)phenyl]-5-nitrofuran-2-carboxamide(1 H),with excellent in vitro UT inhibitory activity at the submicromolar *** half maximal inhibitory concentrations of 1 H against UT-B in mouse,rat,and human erythrocyte were 1.60,0.64,and0.13 mmol/L,*** investigation suggested that 8 mmol/L 1 H more powerfully inhibited UT-A1 at a rate of 86.8%than UT-B at a rate of 73.9%in MDCK cell *** interestingly,we found for the first time that oral administration of 1 H at a dose of 100 mg/kg showed superior diuretic effect in vivo without causing electrolyte imbalance in ***,1 H did not exhibit apparent toxicity in vivo and in vitro,and possessed favorable pharmacokinetic characteristics.1 H shows promise as a novel diuretic to treat hyponatremia accompanied with volume expansion and may cause few side effects.

关键词： Urea transporter inhibitor Diuretic Structure optimization Oral administration

Novel Inhibitors of Lon Protease Reduce Bacterial Persister Formation

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Novel Inhibitors of Lon Protease Reduce Bacterial Persister ...

中国生物化学与分子生物学会第十二届全国会员代表大会暨2018年全国学术会议

作者： Qi Sun Tongqing li runtao li Jianfeng Pei Luhua Lai College of Chemistry and Molecular Engineering and Center for Quantitative BiologyPeking University State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking University

Bacterial persister is a sub-group of special population of bacteria,and has the distinction marks from the ordinary bacteria and resistant *** presence of persister is believed to be closely associated with the recalcitrance and recurrence of chronic infections,and also can increase the prevalence of multidrug-resistant bacteria and extensive resistance *** toxin-antitoxin systems play pivotal role in bacterial persister formation,but few regulators of toxin-antitoxin systems have been ***,we proposed an anti-persister strategy by inhibiting Lon protease,which is essential for antitoxin *** found 43 peptidyl boronic acids as potent covalent inhibitors of *** further demonstrated that Lon inhibition by these compounds dramatically restricted persister formation,which is independent of the antibiotic types used,and works in a wide range of bacterial *** most potent compound,PKUMDL-SQ-B195 reduced the fraction of *** persister with an EC50 of 0.24 ± 0.04 μ*** work demonstrates that Lon protease inhibition is an effective strategy to reduce bacterial persisters,which is promising in developing novel drugs against multidrug-resistant bacteria.

关键词： Lon protease Toxin-antitoxin system Persister Peptidyl boronic acid

In vitro screening of reversible and time-dependent inhibition on CYP3A by TM208 and TM209 in rat liver microsomes

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Acta Pharmaceutica Sinica B 2012年第2期2卷 181-187页

作者： Miaoran Ning liang li Jian li Zaiquan li runtao li Tianyan Zhou Wei Lu State Key Laboratory of Natural and Biomimetic Drugs(Peking University) Beijing 100191China Department of Pharmaceutics School of Pharmaceutical SciencesPeking University Health Science CenterBeijing 100191China Department of Radiation Medicine School of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China

TM208 and TM209,dithiocarbamate derivatives with potential anti-cancer effects,were evaluated in reversible and time-dependent cytochrome P450(CYP)3A inhibition assays in rat liver microsomes using testosterone as probe *** compounds were found to be weak reversible inhibitors and moderate mechanism-based inhibitors of rat *** reversible inhibition on rat CYP3A,the Ki values of competitive inhibition model were 12.10±1.75 and 13.94±1.31 μM,*** time-dependent inhibition,the inactivation constants(K_(l))were 31.93±12.64 and 32.91±15.58 μM,respectively,and the maximum inactivation rates(kinact)were 0.0349770.0069 and 0.0725970.0172 min^(-1) *** findings would provide useful in vitro information for future in vivo DDI studies on TM208 or TM209。

关键词： TM208 TM209 RLMs CYP3A Reversible inhibition TDI DDI

Outcome of multimodal MRI-guided intravenous thrombolysis in patients with stroke with unknown time of onset

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Stroke & Vascular Neurology 2019年第1期4卷 3-7页

作者： Jie Zhao Hongmei Zhao runtao li Jiangtao li Chang liu Juan Lv Yanan li Wei liu Dongpu Ma Huaihai Hao Xinguang Xiao Junzhong liu Yongfeng Yin Rongli liu Qiaoyan Yu Yingjie Wei Pengyan li Yue Wang Runqing Wang Department of Neurology Zhengzhou Central HospitalZhengzhouChina Stroke Center Zhengzhou Central HospitalZhengzhouChina Department of Imaging Zhengzhou Central HospitalZhengzhouChina Emergency Department Zhengzhou Central HospitalZhengzhouChina

Objective Intravenous tissue plasminogen activator(tPA)is the standard therapy for patients with acute ischaemic stroke(AIS)within 4.5 hours of *** trials have expanded the endovascular treatment window to 24 *** investigated the efficacy and safety of using multimodal MRI to guide intravenous tPA treatment for patients with AIS of unknown time of onset(UTO).Methods Data on patients with AIS with UTO and within 4.5 hours of onset were *** elements collected and analysed included:demographics,National Institutes of Health Stroke Scale(NIHSS)score at baseline and 2 hours,24 hours,7 days after thrombolysis and before discharge,the modified Rankin Scale(mRS)score at 3 months after discharge,imaging findings and any adverse *** Forty-two patients with UTO and 62 in control group treated within 4.5 hours of onset were treated with intravenous *** NIHSS scores after thrombolysis and/or before discharge in UTO group were significantly improved compared with the baseline(p0.05).Utilising the non-inferiority test,to compare mRS scores(0-2)at 3 months between the two groups,the difference was 5.2%(92%CI,OR 0.196).Patients in the UTO group had mRS scores of 0-2,which were non-inferior to the control *** incidence of adverse events was *** Utilising multimodal MRI to guide intravenous only thrombolysis for patients with AIS with UTO was safe and *** those patients with AIS between 6 and 24 hours of time of onset but without large arterial occlusion,intravenous thrombolysis could be considered an option.

关键词： intravenous patients thrombolysis

Synthesis of Oxindoles by Metal-free Oxidative Arylalkylation of Activated Alkenes Involving a Tandem C(sp3)-H/C(sp2)-H Activation/Cyclization Process

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Synthesis of Oxindoles by Metal-free Oxidative Arylalkylatio...

中国化学会全国第十一届有机合成化学学术研讨会

作者： Shucheng Wang Xuhu Huang Bowen li Zemei Ge Xin Wang runtao li State key Laboratory of Nature and Biomimetic Drugs School of Pharmaceutical SciencesPeking University

In recent years,several groups reported the synthesis oxindoles via C(sp)-C(sp)bond formation reactions involving free-radical-initiated sp-hybridized C-H bond activation *** examples involving the arylalkylation of activated alkenes through metal-free oxidative reactions are ***,we have developed a novel metal-free tandem oxidative cyclization reaction of activated alkenes mediated by *** method possesses remarkable advantages:good to excellent yields;self-regulating,safe,and highly scalable;electron-donating,electron-withdrawing and heteroatom-containing groups can be tolerated.

关键词： oxindoles metal free xanthate radical

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《史记》车舆类名物词与秦汉车制

河南社会科学 2009年第4期17卷 157-159页

作者：李润桃安阳师范学院文学院河南安阳455000

《史记》车舆类名物词数量众多,特点鲜明。它们有的是各种车舆的名称,有的是车舆构件的名称,还有的是车舆装饰品或附属物的名称。全面考察、整理《史记》车舆类名物词,运用义素分析法梳理并分析了这些车舆类名物词系统的层次性,能洞悉... 详细信息

《史记》车舆类名物词数量众多,特点鲜明。它们有的是各种车舆的名称,有的是车舆构件的名称,还有的是车舆装饰品或附属物的名称。全面考察、整理《史记》车舆类名物词,运用义素分析法梳理并分析了这些车舆类名物词系统的层次性,能洞悉秦汉时期的车马制度及其文化内涵。

关键词：《史记》车舆名物词车马制度

Chrial Primary Diamine Catalyzed Asymmetric Direct Vinylogous Michael Addition of α,β-Unsaturated γ-Butyrolactams with Chalcones

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Chrial Primary Diamine Catalyzed Asymmetric Direct Vinylogou...

中国化学会第九届全国有机化学学术会议

作者： Dawei Yin Xiaolei Du Zemei Ge Xin Wang runtao li State Key Laboratory of Nature and Biomimetic Drugs School of Pharmaceutical Sciences Peking University

＜正＞Chiralγ-butyrolactams are common and important fragments in natural products and biologically active compounds,[1]and they are very significant synthetic intermediates as well.[2]Hence,many efforts have been made for the synthesis of structurally diverse family of 5-substituted butyrolactam derivatives,among which the direct vinylogous Michael addition ofα,β-unsaturatedγ-butyrolactam

关键词： α,β-unsaturated γ-butyrolactam Asymmetric Michael addition chrial primary diamine

Cascade Synthesis of Spirooxindole δ-Lactone Derivatives through N-Aryl hydroxymethylacrylamides with Xanthates

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Cascade Synthesis of Spirooxindole δ-Lactone Derivatives th...

中国化学会第九届全国有机化学学术会议

作者： Shucheng Wang Xuhu Huang Yanzhao Wen Zemei Ge Xin Wang runtao li State Key Laboratory of Nature and Biomimetic Drugs School of Pharmaceutical Sciences Peking University

The spirooxindoles are among the most privileged scaffolds in medicinal chemistry.1,2]However,there is only one report on the synthesis of spirooxindoleδ-lactones,thoughδ-lactone are vital and useful subunit in many bioactive natural products.3]Meanwhile,the cascade reaction has received much attention because the ability to undertake more than one synthetic step in a reaction

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The spirocyclopiperazinium salt compound LXM-15 alleviates chronic inflammatory and neuropathic pain in mice and rats

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Journal of Chinese Pharmaceutical Sciences 2019年第6期28卷 371-380页

作者： Ning li Yingying liang Qi Sun Yimin Jiang runtao li Jia Ye Department of Molecular and Cellular Pharmacology School of Pharmaceutical SciencesPeking University Health ScienceCenterBeijing100191China Department of Chemical Biology School of Pharmaceutical SciencesPeking University Health Science CenterBeijing100191China Department of Medical and Healthy Analysis Center Peking University Health Science CenterBeijing100191China

In the present study,we aimed to evaluate the effect of the spirocyclopiperazinium salt compound LXM-15 on chronic inflammatory pain and chronic neuropathic pain induced by complete Freund’s adjuvant(CFA)or chronic constriction injury(CCI)in mice and *** results showed that administration with LXM-15 significantly reduced paw edema and ankle swelling and increased the mechanical withdrawal threshold and paw withdrawal latency after CFA injection in ***-15 significantly alleviated the mechanical allodynia and thermal hyperalgesia in CCI *** effect was abolished by pretreatment with hexamethonium(a peripheral nAChR antagonist)or methyllycaconitine citrate(anα7 nAChR antagonist).Furthermore,LXM-15 significantly inhibited the phosphorylation of JAK2 and STAT3,and suppressed the expressions of TNF-αand c-fos in dorsal root ganglia of CCI ***,we reported that LXM-15 relieved chronic inflammatory pain in CFA mice and chronic neuropathic pain in CCI *** underlying mechanism might be related to the activation of peripheralα7 nicotinic receptor,further inhibiting JAK2/STAT3 signaling pathway,and eventually suppressing the expressions of TNF-αand c-fos.

关键词： Spirocyclopiperazinium salt compound LXM-15 Chronic pain α7 nicotinic receptor JAK2/STAT3 signaling pathway