Arzneimittel-Forschung-Drug Research最新文献_第3页

Synthesis, anti-hypertensive effect of a novel angiotensin II AT1 receptor antagonist and its anti-tumor activity in prostate cancer. 新型血管紧张素II AT1受体拮抗剂的合成、降压作用及其在前列腺癌中的抗肿瘤活性

Arzneimittel-Forschung-Drug Research Pub Date : 2012-12-01 Epub Date: 2012-11-30 DOI: 10.1055/s-0032-1329952

Y-J Da, W-D Yuan, L-F Zhu, Z-L Chen

{"title":"Synthesis, anti-hypertensive effect of a novel angiotensin II AT1 receptor antagonist and its anti-tumor activity in prostate cancer.","authors":"Y-J Da, W-D Yuan, L-F Zhu, Z-L Chen","doi":"10.1055/s-0032-1329952","DOIUrl":"https://doi.org/10.1055/s-0032-1329952","url":null,"abstract":"Since the first non-peptide Ang II receptor antagonist was originally reported, it has become the most common target in the development of new treatments for hypertension. In recent years, all components of the classical RAS have been reported in the prostate, these results suggest the possibility that ARB is a novel therapeutic class of agents for prostate cancer. In this study, a new compound 2-(4-((2-propyl-5-nitro-1H-benzo[d]imidazol-1-yl) methyl)-1H-indol-1-yl) benzoic acid was synthesized and evaluated as a novel angiotensin II AT1 receptor antagonist by radioligand binding assays, anti-hypertensive assays in vivo and oral acute toxicity test. MTT assays and tests in nude mice were used to demonstrate its anti-tumor activity. This new compound showed high affinity to AT1 receptor and anti-hypertensive activity in spontaneously hypertensive rats and renal hypertensive rats. Moreover, in human prostate cancer cells and in athymic nude mice bearing human prostate cancer cells, we observed this new compound had an efficient antiproliferative activity in vitro and anti-tumor activity in vivo. The preliminary pharmacological characteristics with oral acute toxicity test suggested that this new compound can be considered as a candidate for both anti-hypertensive and anti-tumor drug.","PeriodicalId":56084,"journal":{"name":"Arzneimittel-Forschung-Drug Research","volume":"62 12","pages":"637-43"},"PeriodicalIF":0.0,"publicationDate":"2012-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1055/s-0032-1329952","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31091441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 7

Simultaneous determination of methotrexate, dasatinib and its active metabolite N- deshydroxyethyl dasatinib in rat plasma by LC-MS/MS: method validation and application to pharmacokinetic study. LC-MS/MS同时测定大鼠血浆中甲氨蝶呤、达沙替尼及其活性代谢物N-去羟乙基达沙替尼:方法验证及在药动学研究中的应用

Arzneimittel-Forschung-Drug Research Pub Date : 2012-12-01 Epub Date: 2012-11-08 DOI: 10.1055/s-0032-1327702

S R S Thappali, K V S Varanasi, S Veeraraghavan, S K V S Vakkalanka, M Khagga

{"title":"Simultaneous determination of methotrexate, dasatinib and its active metabolite N- deshydroxyethyl dasatinib in rat plasma by LC-MS/MS: method validation and application to pharmacokinetic study.","authors":"S R S Thappali, K V S Varanasi, S Veeraraghavan, S K V S Vakkalanka, M Khagga","doi":"10.1055/s-0032-1327702","DOIUrl":"https://doi.org/10.1055/s-0032-1327702","url":null,"abstract":"Dasatinib is a multi-kinase inhibitor that potently inhibits Bcr-Abl, Src family and platelet-derived growth factor receptor kinases. Methotrexate is an antimetabolite and antifolate drug. Clinical trials utilizing a combination of dasatinib and methotrexate in patients with Philadelphia chromosome positive and/or Bcr-Abl positive acute lymphoblastic leukemia are currently ongoing. A need therefore exists to develop a sensitive analytical method for determination of dasatinib and methotrexate in plasma.To estimate methotrexate, dasatinib and its active metabolite N-deshydroxyethyl dasatinib simultaneously using liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) in Wistar rat plasma.The analytes were extracted by using liquid-liquid extraction procedure and separated on a reverse phase C18 column (50 mm×3 mm i.d., 4.6 µ) using methanol: 2 mM ammonium acetate buffer, pH 4.0 as mobile phase at a flow rate 1 mL/min in gradient mode. Selective reaction monitoring was performed using the transitions m/z 455.0>175.0, 488.1 > 401.0, 444.26>401.0, and 271.1>- 155.0 to quantify methotrexate, dasatinib, N-deshydroxyethyl dasatinib and tolbutamide respectively.The method was validated over the concentration range of 1-1 000 ng/mL and the lower limit of quantitation was 1 ng/mL. The recoveries from spiked control samples were > 79% for all analytes and internal standard Intra- and Interday accuracy and precision of validated method were within the acceptable limits of < 15% at all concentration.The quantitation method was successfully applied for simultaneous estimation of methotrexate, dasatinib and N- deshydroxyethyl dasatinib in a pharmacokinetic study in Wistar rats.","PeriodicalId":56084,"journal":{"name":"Arzneimittel-Forschung-Drug Research","volume":"62 12","pages":"624-30"},"PeriodicalIF":0.0,"publicationDate":"2012-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1055/s-0032-1327702","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31038685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 15

Synthesis, biological activity and molecular modeling of 4-fluoro-N-[ω-(1,2,3,4-tetrahydroacridin-9-ylamino)-alkyl]-benzamide derivatives as cholinesterase inhibitors. 作为胆碱酯酶抑制剂的4-氟- n- [ω-(1,2,3,4-四氢吖啶-9-氨基)-烷基]-苯酰胺衍生物的合成、生物活性和分子模型。

Arzneimittel-Forschung-Drug Research Pub Date : 2012-12-01 Epub Date: 2012-11-15 DOI: 10.1055/s-0032-1329963

P Szymański, M Markowicz, M Bajda, B Malawska, E Mikiciuk-Olasik

{"title":"Synthesis, biological activity and molecular modeling of 4-fluoro-N-[ω-(1,2,3,4-tetrahydroacridin-9-ylamino)-alkyl]-benzamide derivatives as cholinesterase inhibitors.","authors":"P Szymański, M Markowicz, M Bajda, B Malawska, E Mikiciuk-Olasik","doi":"10.1055/s-0032-1329963","DOIUrl":"https://doi.org/10.1055/s-0032-1329963","url":null,"abstract":"The aim of this study was to synthesize and determine the biological activity of new derivatives of 4-fluorobenzoic acid and tetrahydroacridine towards inhibition of cholinesterases. Compounds were synthesized in condensation reaction between 9-aminoalkyl-tetrahydroacridines and the activated 4-fluorobenzoic acid. Properties towards inhibition of acetyl- and butyrylcholinesterase were estimated according to Ellman's spectrophotometric method. Among synthesized compounds the most active were compounds 4a and 4d. These compounds, in comparison with tacrine, were characterized by the similar values of IC50. Among all obtained compounds, 4d presented the highest selectivity towards inhibition of acetylcholinesterase. Molecular modeling studies revealed that all derivatives presented similar extended conformation in the gorge of acetylcholinesterase, however, there were 2 main conformations in the active center of butyrylcholinesterase: bent and extended conformation.","PeriodicalId":56084,"journal":{"name":"Arzneimittel-Forschung-Drug Research","volume":"62 12","pages":"655-60"},"PeriodicalIF":0.0,"publicationDate":"2012-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1055/s-0032-1329963","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31051890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 7

A validated HPLC method for the determination of eriocalyxin B in plasma and its application to pharmacokinetic studies. 高效液相色谱法测定血药浓度及其在药动学研究中的应用。

Arzneimittel-Forschung-Drug Research Pub Date : 2012-12-01 Epub Date: 2012-11-15 DOI: 10.1055/s-0032-1329986

Z Wang, Q Yuan, J-H Sun, Z Cui, H-Y Chen, H Wu, J-x Chen

{"title":"A validated HPLC method for the determination of eriocalyxin B in plasma and its application to pharmacokinetic studies.","authors":"Z Wang, Q Yuan, J-H Sun, Z Cui, H-Y Chen, H Wu, J-x Chen","doi":"10.1055/s-0032-1329986","DOIUrl":"https://doi.org/10.1055/s-0032-1329986","url":null,"abstract":"The purpose of this study was to determine EriB in plasma by using the method of HPLC and collect the preclinical pharmacokinetic parameters of EriB.The analysis involved a simple liquid-liquid extraction. After making alkaline with NaOH, plasma was extracted with diethyl ether and the organic extract was then evaporated. From there, the residue was reconstituted in to the mobile phase. Chromatographic separation was achieved on the C18 column using acetonitrile and 0.1% triethylamine as mobile phase delivered at 1.0 ml/min. The UV detector wavelength was set at 233 nm. Standard curves were linear over the concentration range of 50-2 500 ng/ml.The mean predicted concentrations of the quality control (QC) samples deviated by less than 3% from the corresponding nominal values; the intra-assay and inter-assay precision of the assay were within 10% relative standard deviation. The extraction recovery of EriB was more than 80%.The developed method has been applied to the pharmacokinetic study of EriB in rats.","PeriodicalId":56084,"journal":{"name":"Arzneimittel-Forschung-Drug Research","volume":"62 12","pages":"666-9"},"PeriodicalIF":0.0,"publicationDate":"2012-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1055/s-0032-1329986","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31051891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

The effect of ethyl alcohol on the function of spatial memory in rats. 乙醇对大鼠空间记忆功能的影响。

Arzneimittel-Forschung-Drug Research Pub Date : 2012-12-01 Epub Date: 2012-10-31 DOI: 10.1055/s-0032-1327701

P Ratajczak, K Kus, Z Jarmuszkiewicz, A Woźniak, E Nowakowska

引用次数: 5

Leave-one-out procedure in the validation of elimination rate constant analysis. 消除率常数分析验证中的留一法。

Arzneimittel-Forschung-Drug Research Pub Date : 2012-12-01 Epub Date: 2012-11-30 DOI: 10.1055/s-0032-1331194

T Grabowski, J J Jaroszewski, M Sasinowska-Motyl

{"title":"Leave-one-out procedure in the validation of elimination rate constant analysis.","authors":"T Grabowski, J J Jaroszewski, M Sasinowska-Motyl","doi":"10.1055/s-0032-1331194","DOIUrl":"https://doi.org/10.1055/s-0032-1331194","url":null,"abstract":"Many registration agencies and other organizations define how to calculate the elimination rate constant (kel) value. No validation procedures have been introduced to verify the correct selection of the concentration-time (C-T) points used for the kel calculation. The purpose of this paper is to discover whether kel analysis can be subjected to the condensed validation procedure and what acceptance criteria should be adopted for such a procedure. For the analysis, data collected during bioequivalence studies of 4 drugs were selected, including 2 highly lipophilic drugs (itraconazole, atorvastatin) and 2 weakly lipophilic drugs (trimetazidine, perindopril). Pharmacokinetic calculations were performed with the use of WinNonlin Professional v 5.3. Internal validation of the kel analysis using leave-one-out cross-validation was performed. The present analysis proves that the C-T selection process for the kel calculations cannot be automated. In each of the analysed data series there were such C-T sequences that did not meet even one of the validation criteria. This paper proposes 3 validation criteria which need to be met in order to confirm the optimal selection of C-T data to calculate kel: Q 2≥0.6, R2≥ 0.85, Q 2-R2<0.3, were Q 2 - squared cross-validated correlation coefficient, R2 - coefficient of determination). Application of the validation procedure for the kel analysis under discussion proves the accuracy of the calculations, even if repeated kel analysis is based on a different sequence of points in the elimination phase.","PeriodicalId":56084,"journal":{"name":"Arzneimittel-Forschung-Drug Research","volume":"62 12","pages":"682-9"},"PeriodicalIF":0.0,"publicationDate":"2012-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1055/s-0032-1331194","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31091443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 5

The inhibition of monoamine oxidase by 8-(2-phenoxyethoxy)caffeine analogues. 8-(2-苯氧乙氧基)咖啡因类似物对单胺氧化酶的抑制作用。

Arzneimittel-Forschung-Drug Research Pub Date : 2012-11-01 Epub Date: 2012-08-31 DOI: 10.1055/s-0032-1323662

B Strydom, J J Bergh, J P Petzer

引用次数: 18

Synthesis and biological evaluation of a 6-aminofuro[3,2-c]pyridin-3(2H)-one series of GPR 119 agonists. 6-氨基[3,2-c]吡啶-3(2H)- 1系列GPR 119激动剂的合成及生物学评价。

Arzneimittel-Forschung-Drug Research Pub Date : 2012-11-01 Epub Date: 2012-09-12 DOI: 10.1055/s-0032-1323760

M Sakairi, M Kogami, M Torii, Y Kuno, Y Ohsawa, M Makino, D Kataoka, R Okamoto, T Miyazawa, M Inoue, N Takahashi, S Harada, N Watanabe

{"title":"Synthesis and biological evaluation of a 6-aminofuro[3,2-c]pyridin-3(2H)-one series of GPR 119 agonists.","authors":"M Sakairi, M Kogami, M Torii, Y Kuno, Y Ohsawa, M Makino, D Kataoka, R Okamoto, T Miyazawa, M Inoue, N Takahashi, S Harada, N Watanabe","doi":"10.1055/s-0032-1323760","DOIUrl":"https://doi.org/10.1055/s-0032-1323760","url":null,"abstract":"G protein-coupled receptor 119 (GPCR 119 (GPR119)) agonists have received considerable attention as a promising therapeutic option for treatment of type 2 diabetes mellitus. GPR119 is one of the GPCRs expressed in pancreatic islet β-cells and its activation enhances stimulation of insulin secretion in a glucose-dependent manner. We have recently described a series of 6-amino-1H-indan-1-ones as potent, selective, and orally bioavailable GPR119 agonists with an amino group that plays important roles not only in their drug-like properties, such as high aqueous solubility, but also in their potent agonistic activity. However, many of these compounds displayed strong to moderate inhibition of human ether-à-go-go related gene channel. Attenuation of the basicity of the amino group by replacing the adjacent benzene ring with electron-deficient heteroaromatic rings provided several heterocyclic cores among which 6-aminofuro[3,2-c]pyridin-3(2H)-one was selected as a promising scaffold. Further optimization around the side chain moiety led to the discovery of 17i, which showed not only strong human GPR119 agonistic activity (EC50=14 nM), but also beneficial effects on gastric emptying and plasma total glucagon-like peptide-1 levels in mice.","PeriodicalId":56084,"journal":{"name":"Arzneimittel-Forschung-Drug Research","volume":"62 11","pages":"537-44"},"PeriodicalIF":0.0,"publicationDate":"2012-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1055/s-0032-1323760","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30901263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Some novel anticonvulsant agents derived from phthalazinedione. 从酞嗪二酮中提取的几种新型抗惊厥药。

Arzneimittel-Forschung-Drug Research Pub Date : 2012-11-01 Epub Date: 2012-09-06 DOI: 10.1055/s-0032-1323758

M F Zayed, R R Ayyad

引用次数: 10

CYP2C9*3(1075A>C), MDR1 G2677T/A and MDR1 C3435T are determinants of inter-subject variability in fluvastatin pharmacokinetics in healthy Chinese volunteers. CYP2C9*3(1075A>C)、MDR1 G2677T/A和MDR1 C3435T是影响中国健康志愿者氟伐他汀药代动力学个体间变异性的决定因素。

Arzneimittel-Forschung-Drug Research Pub Date : 2012-11-01 Epub Date: 2012-08-31 DOI: 10.1055/s-0032-1323696

Q Zhou, Z-r Ruan, H Yuan, S Zeng

{"title":"CYP2C9*3(1075A>C), MDR1 G2677T/A and MDR1 C3435T are determinants of inter-subject variability in fluvastatin pharmacokinetics in healthy Chinese volunteers.","authors":"Q Zhou, Z-r Ruan, H Yuan, S Zeng","doi":"10.1055/s-0032-1323696","DOIUrl":"https://doi.org/10.1055/s-0032-1323696","url":null,"abstract":"To evaluate the impact of single-nucleotide polymorphisms (SNPs) in CYP2C9, MDR1, SLCO1B1 and ABCG2 on the pharmacokinetics of fluvastatin in Chinese participants.A pharmacokinetic study of fluvastatin (single dose 40 mg) was conducted in 12 healthy Chinese volunteers. Plasma concentrations of fluvastatin were determined by a high-performance liquid chromatography with fluorescence detection. Pharmacokinetic parameters were calculated by non-compartmental method. The SNPs were determined by TaqMan®(MGB) genotyping assay.Effect of CYP2C9*3 (c.1075A>C) on area under the plasma concentration-time curve (AUC) of fluvastatin was statistically significant. Heterozygous variant (C/A) carriers had higher AUC values compared to homozygous wild type (A/A) carriers (922.03±148.17 µg · h · L - 1 vs. 496.00±168.93 µg · h · L - 1, P=0.003092). The elimination half-life (T 1/2) values of fluvastatin were longer in MDR1 2677non-G carriers than in MDR1 2677G carriers (2.21±0.47 h vs. 1.25±0.62 h, P=0.02319), and also they were longer in MDR1 1236T-2677non-G-3435T carriers than in MDR1 1236C-2677G-3435C carriers (2.31±0.51 h vs. 1.32±0.62 h, P=0.03320). MDR1 C3435T polymorphism had a significant effect on maximal plasma concentrations (C max) of fluvastatin. Mutation gene T (TT+CT) carriers had higher C max values compared to homozygous wild type (C/C) carriers (688.54±142.67 µg · L - 1 vs. . 413.78±177.83 µg · L - 1, P=0.01448). Some SNPs such as MDR1 C1236T, ABCG2 c.34G>A, ABCG2 c.421C>A, SLCO1B1 c.388 A>G, SLCO1B1 c.521 T>C, SLCO1B1 c.571 T>C and SLCO1B1 c.597 C>T have no significant effects on fluvastatin pharmacokinetics.CYP2C9*3(1075A>C), MDR1 C3435T and MDR1 G2677T/A were determinants of inter-subject variability in fluvastatin pharmacokinetics in healthy Chinese volunteers.","PeriodicalId":56084,"journal":{"name":"Arzneimittel-Forschung-Drug Research","volume":"62 11","pages":"519-24"},"PeriodicalIF":0.0,"publicationDate":"2012-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1055/s-0032-1323696","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30873832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 17