Journal of Chinese Pharmaceutical Sciences

Design, synthesis, and in vitro activity of methylisoxazole/isothiazole amides as BACE1 inhibitors

Peng Lv, Can Li, Yan Niu, Hongyue Li, Tongliang Zhou, Fengrong Xu, Lei Liang, Chao Wang, Ping Xu

2018, 27(3): 143-158. DOI: 10.5246/jcps.2018.03.016

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Based on the structure of compound B51 (IC₅₀ = 37.4 μM), which was discovered as hit in a previous virtual screen, a series of methylisoxazole/isothiazole amide derivatives were designed and synthesized as BACE1 inhibitors. The methoxyphenylpyrimidone fragment of B51 was transformed into a methoxyphenylmethylisoxazole/isothiazole moiety to reduce the molecular weight while retaining the ability to fit into the S₁' and S₂' subpocket of BACE1 as predicted by docking studies. The effects of BACE1 inhibition and the structure-activity relationships were analyzed. Among all 20 designed compounds, 5t exhibited almost 10-fold improved potency (IC₅₀ = 5.33 μM) compared to B51 in the BACE1 inhibition assay. Additionally, it has exhibited “rapid binding, slow dissociation” kinetics in SPR analysis, suggesting a longer inhibitory effect than B51. All acquired methylisoxazole/isothiazole derivatives were small in size and safe to normal cells, which allow them represent a novel scaffold for BACE1 inhibitor design.

Design, synthesis and antitumor activity evaluation of novel 2,6-dichloro-3,5-dinitrotoluene derivatives

Jiayuan Jiao, Hao Hu, Siyuan Wei, Wanqiu Wang, He Lin, Baoshan Chai

2018, 27(3): 159-169. DOI: 10.5246/jcps.2018.03.017

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A series of novel 2,6-dichloro-3,5-dinitrotoluene derivatives were designed, synthesized in the present study, and their antitumor activities against five cell lines (A431, HepG2, A549, HT-29 and HEK-293) were tested. Most of the compounds exhibited moderate-to-significant cytotoxicity and high selectivity against one or more cell lines in comparison with cisplatin. Studies on their preliminary structure-activity relationships (SARs) indicated that compounds containing phenyl (piperazin-1-yl) methanone groups, especially chlorine atom at 4-position of the phenyl ring, were more effective. Compound 4g was found to be the most potent derivative with IC₅₀values of 1.04, 3.20, 6.93, 4.10 and 20.15 μmol/L against A431, Hep G2, A549, HT-29 and HEK-293 cell lines, respectively, which was better than positive control cisplatin, one of the most clinically used chemotherapeutic drugs.

Effect of berberine against cerebral ischemia and reperfusion involving in the methylation of PPARγ promoter

Yunong Pang, Yinwen Liang, Yugang Wang, Fan Lei, Zhiyi Yuan, Dongming Xing, Jun Li, Lijun Du

2018, 27(3): 170-182. DOI: 10.5246/jcps.2018.03.018

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Cerebral ischemia has higher incidence and causes irreversible damage to people. As a traditional drug for anti-inflammation, berberine (BBR) has recently been reported to have protective effect against cerebral ischemia. However, the mechanism has not been explored thoroughly. By employing in vivo and in vitro models for cerebral ischemia and reperfusion, we studied the mechanism of BBR against the ischemia-reperfusion. We found that BBR regulated the expression of peroxisome proliferator-activated receptor (PPARγ) in a specific way upon ischemia-reperfusion injury. BBR enhanced the PPARγ expression during cerebral ischemia-reperfusion. By inhibiting PPARγ activity uisng GW9662, a PPARγ inhibitor, we confirmed that BBR protected the mouse brain against the ischemia in a PPARγ-dependent mechanism. In addition, we found that BBR reduced the overall global methylation, declined the expressions of DNMT1 (DNA methyltransferases 1) and DNMT3a (DNA methyltransferases 3a) in the ischemia-reperfusion and reduced the methylation of PPARγ promoter region. Therefore, our data suggested that PPARγ was one of major targets of BBR, and such BBR-induced PPARγ expression during cerebral ischemia and reperfusion might be correlated to the reduced methylation of PPARγ promoter.

Effects and mechanisms of Artemisia argyi essential oil on monocrotaline-induced pulmonary hypertension in rats

Yin Ying, Yunfeng Sun, Hongchun Li, Bo Yang, Hui Wang, Qingmei Wu, Ping Huang

2018, 27(3): 183-192. DOI: 10.5246/jcps.2018.03.019

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In the present study, we aimed to investigate the effects of Artemisia argyi essential oil (AO) on pulmonary hypertension (PH)inducedbymonocrotaline(MCT)andtoexploretheunderlying mechanism.A total of 80 Sprague-Dawley ratswererandomlydividedintofourgroups as follows:controlgroup, modelgroup,bosentan(0.1g/kg)groupandAO(0.1g/kg)group.After30dofexperiment, hemodynamicparameters,lungandrightventricle hypertrophy indexweredetermined. HEand Immunohistochemistrystainingoflungs were performedto detectthe injuriesandprotein expressions. Theresultsshowedthatlevels of mPAP,mRVP,maxRVP,wW,LI,RV and RVHI as well asthe expressionsofNF-κBp65andα-SMA were increased,smallpulmonaryarterythickened, the cavity of the arteriole narrowed, and there was marked infiltration of inflammatory cells in lungs of rats receiving MCT compared with the normal group. After the administration of AO, the levels of mPAP and mRVP were significantly decreased,and the wW, LI, LV+S and pulmonary arterial remodeling were markedly improved. The expression levels of NF-κB p65 and α-SMAwerereduced by AOcomparedwiththe modelgroup.Ourresultssuggestedthat AOreduced the progressionof PH induced byMCTthroughinhibiting the expressions of NF-κB p65 and α-SMA.

Development and validation of an HPLC assay for the quantitation of mefunidone, a novel derivative of pirfenidone, and an initial pharmacokinetics study in liver microsomes

Yanfen Chen, Meng Sun, Shixi Zhang, Zeneng Cheng, Gaoyun Hu, Qubo Zhu

2018, 27(3): 193-200. DOI: 10.5246/jcps.2018.03.020

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本研究开发了一种简单可靠的HPLC-UV方法用于美氟尼酮的测定。生物分析步骤包括从500 μL肝微粒体系统中通过甲醇沉淀蛋白质提取美氟尼酮。色谱条件:色谱柱为Agilent TC-C₁₈柱(4.6 mm×250 mm, 5 μm), 流动相为10 mM甲酸铵(用10%的甲酸调PH至2.9)–乙腈(70:30, v/v),流速为1.0 mL/min, UV检测波长设定在245 nm。美氟尼酮和吡非尼酮(内标物)分别在6.0和9.7分钟洗脱,总运行时间为12分钟。根据美国食品和药物管理局生物分析指南,进行了方法验证,结果符合验收标准。美氟尼酮在肝微粒体中的标准曲线在0.5–16 μg/mL范围内呈线性关系。美氟尼酮内和外间精确度低于9.0％,偏差在±10.0％以内。美氟尼酮在肝微粒体中孵育后,该方法成功应用于药代动力学研究。

Development and validation of an HPLC-UV method for the separation of entecavir optical isomers

Dan Huang, Daolin Zhang, Nana Wang, Xinhui Jiang

2018, 27(3): 201-208. DOI: 10.5246/jcps.2018.03.021

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A simple and effective high-performance liquid chromatography with ultraviolet detection (HPLC-UV) method was established to determine entecavir optical isomers. With 3 chiral carbon atoms, entecavir had 7 optical isomers, including 6 diastereoisomers and 1 enantiomer. The separations were performed on a Symmetrix ODS-AQ C₁₈ column (4.6 mm×250 mm, 5 µm) and a Daicel CHIRALPAK AD column (4.6 mm×250 mm,10 µm), respectively. The detection wavelength was set at 254 nm.The limit of detection (LOD) and the limit of quantification (LOQ) of diastereoisomers (diastereoisomer-1, diastereoisomer-2, diastereoisomer-3) were 0.0371, 0.0376, 0.0377, and 0.124, 0.125, 0.126 µg/mL, respectively. The LOD and LOQ of enantiomer were 0.14 and 0.46 µg/mL, respectively. The precision was within 0.36%, 0.44%, 1.04%, and 0.67% for diastereoisomer-1, diastereoisomer-2, diastereoisomer-3, and enantiomer, respectively. The recoveries of enantiomers ranged from 98.4% to 100.5%. The method could be applied to control the quality of entecavir.

The comprehensive influence of firm-level factors on drug product internationalization of Chinese pharmaceutical firms

Xianghong Lin, Hao Hu, Yi Liu, Xiaodong Guan, Jiafang Song, Luwen Shi

2018, 27(3): 209-214. DOI: 10.5246/jcps.2018.03.022

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Drug product internationalization (DPI) can be affected by multiple firm-level factors. However, existing studies mainly focus on a single or several factors and the deviation generated by the factors’ effects on each other has been neglected. We aimed to study the comprehensive influences of firm-level factors on Chinese pharmaceutical firms that chose the DPI mode. Student’s t tests and Chi Square tests were used to explore the differences between firms with or without DPI modes. Then, logistic regression analysis was used to explore the comprehensive impacts of these 16 variables.Through empirical research, we found the factors influencing the DPI mode of Chinese pharmaceutical enterprises and the firm-level factors that influenced DPI mode selection. This study showed that the capacity of enterprise’s innovation and knowledge absorption were related to the mode selection. Moreover, the education of the top management team significantly contributed to the DPI mode selection of pharmaceutical firms. This study also provided theoretical and empirical evidence for pharmaceutical enterprises when choosing their DPI mode.The internationalization of Chinese pharmaceutical firms remained at the early stage. However, the internationalization of drug products from China would affect the international pharmaceutical supply in the long term.

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