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国外医学（药学分册） 2002年第5期29卷 311-312页

作者：李英玉

A convenient synthesis of ezetimibe analogs as cholesterol ab sorption inhibitors

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Chinese Chemical Letters 2010年第1期21卷 67-69页

作者： Ji, Jian Feng Zhang, Hui Bin Huang, Wen Long Qian, Hai Zhou, Jin Pei China Pharmaceut Univ Ctr Drug Discovery Nanjing 210009 Peoples R China China Pharmaceut Univ Dept Med Chem Nanjing 210009 Peoples R China

A convenient method for the synthesis of ezetimibe analogs as cholesterol absorption inhibitors was *** key step in the synthesis was the intramolecular ring formation through Mitsunobu ***,a new series of analogs was... 详细信息

关键词： ezetimibe Synthesis Cholesterol absorption inhibitor

ezetimibe improves hepatic steatosis in relation to autophagy in obese and diabetic rats

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World Journal of Gastroenterology 2015年第25期21卷 7754-7763页

作者： Eugene Chang Lisa Kim Se Eun Park Eun-Jung Rhee Won-Young Lee Ki-Won Oh Sung-Woo Park Cheol-Young Park Department of Nutritional Science and Food Management Ewha Womans University Diabetes Research Institute Kangbuk Samsung Hospital Sungkyunkwan University School of Medicine Division of Endocrinology and Metabolism Department of Internal Medicine Kangbuk Samsung Hospital Sungkyunkwan University School of Medicine

AIM: To investigate whether ezetimibe ameliorates hepatic steatosis and induces autophagy in a rat model of obesity and type 2 diabetes. METHODS: Male age-matched lean control LETO and obese and diabetic OLETF rats were administered either PBS or ezetimibe(10 mg/kg per day) via stomach gavage for 20 wk. Changes in weight gain and energy intake were regularly monitored. Blood and liver tissue were harvested after overnight fasting at the end of study. Histological assessment was performed in liver tissue. The concentrations of glucose, insulin, triglycerides(TG), free fatty acids(FFA), and total cholesterol(TC) in blood and TG, FFA, and TG in livertissue were measured. m RNA and protein abundance involved in autophagy was analyzed in the liver. To investigate the effect of ezetimibe on autophagy and reduction in hepatic fat accumulation, human Huh7 hepatocytes were incubated with ezetimibe(10 μmol/L) together with or without palmitic acid(PA, 0.5 mmol/L, 24 h). Transmission electron microscopy(TEM) was employed to demonstrate effect of ezetimibe on autophagy formation. Autophagic flux was measured with bafilomycin A1, an inhibitor of autophagy and following immunoblotting for autophagy-related protein ***: In the OLETF rats that received ezetimibe(10 mg/kg per day), liver weight were significantly decreased by 20% compared to OLETF control rats without changes in food intake and body weight(P ezetimibe-administrated OLETF rats were dramatically decreased at least by 30% compared to OLETF controls(P ezetimibe(P ezetimibe(P < 0.05). Likewise, for hepatocytes cultured in vitro,

关键词： Autophagy ezetimibe Hepatic steatosis Nonalcoholic fatty liver disease

Effect of insulin-sensitizing agents in combination with ezetimibe, and valsartan in rats with non-alcoholic fatty liver disease

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World Journal of Gastroenterology 2006年第27期12卷 4369-4376页

作者： Nimer Assy Masha Grozovski Ilana Bersudsky Sergio Szvalb Osamah Hussein Liver Unit Sieff HospitalSafedIsrael and Technion InstituteFaculty of MedicineHaifaIsrael Department of Internal Medicine ASieff HospitalSafedIsrael Ort Braude College KarmielIsrael Department of Pathology Sieff HospitalSafedIsrael Department of Internal Medicine A Sieff HospitalSafedIsrael

AIM： To assess whether treatment with insulinsensitizing agents （ISAs） in combination with ezetimibe and valsartan have greater effect on hepatic fat content and lipid peroxidation compared to monotherapy in the methionine choline-deficient diet （MCDD） rat model of non-alcoholic fatty liver disease （NAFLD）. METHODS： Rats （n = 6 per group） were treated with different drugs, including MCDD only, MCDD diet with either metformin （200 mg/kg）, rosiglitazone （3 mg/kg）, metformin plus rosiglitazone （M＋R）, ezetimibe （2 mg/ kg）, valsartan （2 mg/kg）, or combination of all drugs for a total of 15 wk. Liver histology, lipids, parameters of oxidative stress and TNF-alpha were measured. RESULTS： Fatty liver （FL） rats demonstrated severe hepatic fatty infiltration （〉 91% fat）, with an increase in hepatic TG （＋1263%, P 〈 0.001）, hepatic cholesterol （＋245%, P 〈 0.03）, hepatic MDA levels （＋225%, P 〈 0.001）, serum TNF-alpha （17.8 ＋ 10 vs 7.8 ＋ 0.0, P 〈 0.001）, but a decrease in hepatic alpha tocopherol （-74%, P 〈 0.001） as compared to the control rats. Combination therapy with all drugs produced a significant decrease in liver steatosis （-54%）, hepatic TG （-64%）, hepatic cholesterol （-31%） and hepatic MDA （-70%）, but increased hepatic alpha tocopherol （＋443%） as compared to FL rats. Combination therapy with ISA alone produced a smaller decrease in liver steatosis （-32% vs -54%, P 〈 0.001） and in hepatic MDA levels （-55% vs -70%, P 〈 0.01）, but a similar decrease in hepatic lipids when compared with the all drugs combination. TNF-alpha levels decreased significantly in all treatment groups except in ISA group. CONCLUSION： Combination therapies have a greater effect on liver fat content as compared to monotherapy. Rosiglitazone appears to improve hepatic steatosis to a greater extent than metformin.

关键词： Fatty liver Rosiglitazone Metformin ezetimibe Valsartan Methionine choline-deficient diet Insulin resistance

Merger of ezetimibe and Statin:a Potential Dual Inhibitor

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Chemical Research in Chinese Universities 2011年第2期27卷 232-236页

作者： HE Xing-lian XU Xian-xiu ZHENG Lian-you BAI Xu Center for Combinatorial Chemistry and Drug Discovery School of Pharmaceutical Sciences Jilin University Changchun 130021 P R. China College of Chemistry Jilin University Changchun 130012 P R. China College of Chemistry Northeast Normal University Changchun 130024 P R. China

A potential dual inhibitor（4） for exogenous absorption and endogenic synthesis of cholesterol was designed based on the conjugation of the β-lactam pharmacophore of ezetimibe and the δ-lactone pharmacophore of statins. The merger of ezetimibe and statin 4 was synthesized from p-hydroxybenzaldehyde through a ten-step route. 1H NMR analysis showed existence of four pairs of enantiomers（5.7：5.7：1：1, molar ratio）. And compound 4 was found to lower total glucose（TG） level in rat serum via a high-cholesterol and high-fat feeding experiment.

关键词： Multi-target drug ezetimibe Statin

Effect of ezetimibe on the prevalence of cholelithiasis

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World Journal of Gastroenterology 2012年第40期18卷 5789-5792页

作者： Assaf Stein Doron Hermoni Avishay Elis Fred M Konikoff Department of Gastroenterology and Hepatology University of Tel AvivMeir Medical CenterKfar Saba 44281Israel Department of Family Medicine Clalit Health Services SharonNetanya 42470Israel Department of Medicine A University of Tel AvivMeir Medical CenterKfar Saba 44281Israel

AIM： To investigate the prevalence of cholelithiasis among patients treated with ezetimibe. METHODS： A retrospective, case-control study based on computerized medical records from patients of the Clalit Health Services, Sharon-Shomron region, from 2000 to 2009. Patients 20-85 years of age, who had been treated with ezetimibe and statins or statins only for at least 6 too, and who had an abdominal ultrasound were included in the study. Collected data included age, gender, ezetimibe treatment duration, presence of hypothyroidism or diabetes, and existence of cholelithiasis as determined by ultrasound. Ex- cluded were subjects after gallbladder resection, with hemolysis, myeloproliferative or inflammatory bowel diseases, and those treated with ursodeoxycholic acid and fibrates. Patients treated with statins and ezeti- mibe （study group） were compared to patients treated with statins only （control group）. RESULTS： The study group included 25 patients and the control group 168. All patients in the study were treated with statins. The study group included 13 males （52%） and 12 females （48%）, the control group 76 males （45%） and 92 （55%） females （P = 0.544）. The groups did not differ in age （mean age： 68 ± 8 years, range 53-85 years vs mean age： 71±8 years, range 51-85 years; P = 0.153） or in the rate of dia- betic and hypothyroid patients [11 （44%） vs 57 （33%）, P = 0.347 in the study group and 5 （20%） vs 23 （14%）, P = 0.449 in the control group, respectively]. Patients in the study group were treated with ezetimibe for an average of 798±379 d. Cholelithiasis was found in 4 （16%） patients in the study group and in 33 （20%） patients in the control group （P = 0.666）. CONCLUSION： ezetimibe does not appear to influ- ence the prevalence of gallstones.

关键词： Bile Cholesterol Neiman-Pick Cl-like Re-ceptor Gallstones ezetimibe

Serious drug-induced liver disease secondary to ezetimibe

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World Journal of Gastroenterology 2008年第32期14卷 5098-5099页

作者： José Castellote Javier Ariza Rosa Rota Anna Girbau Xavier Xiol Hepatology and Liver Transplant Unit IdibellHospital Universitario de Bellvitge

ezetimibe is the f irst member of a new family of lipid- lowering drugs that inhibits uptake of dietary and bili- ary cholesterol. It was approved by the FDA in 2002 for hypercholesterolemia alone or in combination with statins. Its use has been spreading over the last years. ezetimibe was considered a safe drug. We report a case of a woman who developed a serious hepatocellular drug-induced liver disease after 4 mo therapy with 10 mg daily of ezetimibe. After withdrawal of the drug, the patient recovered slowly. ezetimibe may produce seri- ous toxic hepatitis and prompt withdrawal is mandatory in case of a signif icant abnormality in liver testing after beginning or during treatment with ezetimibe.

关键词： ezetimibe Hepatitis Drug-induced liverdisease

First synthesis and characterization of key stereoisomers related to ezetimibe

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Chinese Chemical Letters 2014年第8期25卷 1157-1160页

作者： Yun Ren Yan-Jun Duan Ren-Jun Li Yong Deng Li Hai Yong Wu Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry Department of Medicinal Chemistry West China School of PharmacySichuan University

uring the laboratory optimization and the late phase manufacturing studies of the cholesterol absorption inhibitor ezetimibe 1, the formation of several stereoisomers was observed. To study the complete stereoisomer profile of ezetimibe 1, we have synthesized and completely characterized several key stereoisomers of ezetimibe 1 for the first time. This study will provide an access to the reference standard of these stereoisomers and may have some implications in the development of new medicines.

关键词： ezetimibe Related substances Stereoisomers profile Synthesis Characterization

Co-administration of ursodeoxycholic acid with rosuvastatin/ezetimibe in a non-alcoholic fatty liver disease model

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Gastroenterology Report 2022年第1期10卷 440-450页

作者： Sang Hyun Seo Da Hyun Lee Yu Seol Lee Kyung Joo Cho Hye Jung Park Hye Won Lee Beom Kyung Kim Jun Yong Park Do Young Kim Sang Hoon Ahn Soo Han Bae Seung Up Kim Department of Internal Medicine Graduate School of Medicine ScienceBrain Korea 21 ProjectYonsei University College of MedicineSeoulRepublic of Korea Yonsei Liver Center Severance HospitalSeoulRepublic of Korea Severance Biomedical Science Institute Graduate School of Medical ScienceBrain Korea 21 ProjectYonsei University College of MedicineSeoulRepublic of Korea Severance Biomedical Science Institute Yonsei Biomedical Research InstituteYonsei University College of MedicineSeoulRepublic of Korea Department of Internal Medicine Institute of GastroenterologyYonsei University College of MedicineSeoulRepublic of Korea

Background Ursodeoxycholic acid(UDCA),statins,and ezetimibe(EZE)have demonstrated beneficial effects against nonalcoholic fatty liver disease(NAFLD).We investigated the efficacy of the combination of UDCA and the mix of rosuvastatin(RSV)/EZE in the treatment of *** NAFLD mouse models were developed by injecting thioacetamide,fasting,and high-carbohydrate refeeding,highfat diet,and choline-deficient L-amino acid-defined high-fat diet(CDAHFD).Low-dose UDCA(L-UDCA;15 mg/kg)or highdose UDCA(H-UDCA;30 mg/kg)was administered with RSV/*** also employed an in vitro model of NAFLD developed using palmitic acid-treated Hepa1c1c7 *** Co-administration of RSV/EZE with UDCA significantly decreased the collagen accumulation,serum alanine aminotransferase(ALT)levels,and mRNA levels of fibrosis-related markers than those observed in the vehicle group in thioacetamide-treated mice(all P<0.01).In addition,in the group fasted and refed with a high-carbohydrate diet,UDCA/RSV/EZE treatment decreased the number of apoptotic cells and serum ALT levels compared with those observed in the vehicle group(all P<0.05).Subsequently,H-UDCA/RSV/EZE treatment decreased the number of ballooned hepatocytes and stearoyl-CoA desaturase 1(SCD-1)mRNA levels(P=0.027)in the liver of high-fat diet-fed mice compared with those observed in the vehicle *** the CDAHFD-fed mouse model,UDCA/RSV/EZE significantly attenuated collagen accumulation and fibrosis-related markers compared to those observed in the vehicle group(all P<0.05).In addition,UDCA/RSV/EZE treatment significantly restored cell survival and decreased the protein levels of apoptosis-related markers compared to RSV/EZE treatment in palmitic acid-treated Hepa1c1c7 cells(all P<0.05).Conclusion Combination therapy involving UDCA and RSV/EZE may be a novel strategy for potent inhibition of NAFLD progression.

关键词： non-alcoholic fatty liver disease non-alcoholic steatohepatitis ursodeoxycholic acid rosuvastatin ezetimibe

Simultaneous determination of ezetimibe and simvastatin in rat plasma by stable-isotope dilution LC-ESI-MS/MS and its application to a pharmacokinetic study

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Journal of Pharmaceutical Analysis 2014年第4期4卷 286-294页

作者： Sireesha R.Karanam Prakash Katakam Babu R.Chandu Nagiat T.Hwisa Shanta K.Adiki Vimta Life Sciences Alexandria Knowledge ParkGenome ValleyHyderabadAPIndia Faculty of Pharmacy University of ZawiaAl-ZawiyaLibya Nirmala College of Pharmacy GunturIndia

A simple, sensitive and specific liquid chromatography-tandem mass spectrometry method was developed for simultaneous quantification of ezetimibe and simvastatin in rat plasma. The deuterium isotopes： ezetimibe d4 and simvastatin d6 were used as internal standards for ezetimibe and simvastatin, respectively. MS/MS detection involved a switch of electron spray ionization mode from negative to positive at retention time 3.01 rain. Samples were extracted from plasma by liquid-liquid extraction using tertiary butyl methyl ether. Chromatographic separation was achieved with Agilent Eclipse XBD-CIs column using mobile phase that consisted of a mixture of ammonium acetate （pH4.5; 10 mM）-acetonitrile （25：75 v/v）. The method was linear and validated over the concentration range of 0.2--40.0 ng/rnL for simvastatin and 0.05-15.0 ng/mL for ezetimibe. The transitions selected were m/z 408.3→271.1 and m/z 412.0→275.10 for ezetimibe and ezetimibe d4, and m/z 419.30 → 285.20 and rrdz 425.40 →199.20 for simvastatin and simvastatin d6. Intra- and inter-batch precisions for ezetimibe were 1.6-14.8% and 2.1-13.4%; and for simvastatin 0.94-9.56% and 0.79-12%, respectively. The proposed method was sensitive, selective, precise and accurate for the quantification of ezetimibe and simvastatin simultaneously in rat plasma. The method was successfully applied to a pharmacokinetic study by oral co-administration of ezetimibe and simvastatin in SD rats.

关键词： ezetimibe Simvastatin PharmacokineticsRat plasma LC-ESI-MS/MS