Inhibitors of the enkephalin degrading enzymes Modulation of activity of hydroxamate containing compounds by modifications of the C-terminal residue

To further characterize the S′₂ subsite of both the neutral endopeptidase (EC 3.4.24.11, NEP) and aminopeptidase N (EC 3.4.11.2, APN), two enzymes physiologically involved in enkephalin metabolism, a new series of hydroxamate inhibitors containing a cyclic amino acid as the Pi component were synthesized. These amino acids differ by the size of the cycle, the relative position of the functional groups, and their absolute configuration. Highly efficient inhibitors of NEP were obtained whatever the modification on the Pi component, while for APN inhibition, a cyclic β-amino acid was preferred. The most active inhibitors contained a trans cyclopentyl β-amino acid and a Cis or a trans cyclohexyl β-amino acid. When injected intracerebroventricularly in mice, these two latter compounds elicited potent antinociceptive responses on both the jump latency and the fore paw lick times.     

玉米血管紧张素转化酶抑制肽及其降压作用的研究

血管紧张素转化酶对人体血压调节有重要的生理作用。玉米蛋白粉中的血管紧张素转化酶抑制肽（angiotensinⅠconverting enzyme inhibitory peptides,ACEIP）通过抑制ACE的活性产生明显的降压作用。本文详细介绍了玉米ACEIP的作用机制、分离纯化工艺、检测和评价,简单介绍了其结构性质,比较分析了给药途径的影响,并对其应用前景进行了展望。     

H-Gly-Hisψ(NHCO)Lys-OH,partially modified retro-inverso analogue of the growth factor glycyl-L-histidyl-L-lysine with enhanced enzymatic stability

A partially retro-inverso analogue of the natural growth factor GHK was synthesized, in which the —CONH— bond between histidine and lysine was modified as —NHCO—. This modification is not expected to perturb the spatial distribution of the side-chains, and therefore the binding processes, compared to the native peptide. In the synthesis of the analogue two possible systems for deblocking of N^π-Born group of histidine have been applied and compared. An alternative method is also described for the incorporation of malonyllysine into the peptide chain. When evaluated with respect to resistance toward degradation by human plasma in vitro, the new peptide analogue showed approximately a ten-fold increase in stability versus the parent peptide.     

血管紧张素转换酶抑制剂治疗阿尔茨海默病的效果

目的观察血管紧张素转换酶抑制剂(ACEI)治疗阿尔茨海默病(AD)痴呆患者的精神行为症状、认知功能损害的效果。方法 52例AD痴呆患者口服盐酸卡托普利治疗12周,采用神经精神科问卷(NPI)评定患者的精神行为症状变化,采用简易智能状态检查量表评定患者的认知功能变化。结果治疗12周后,除情感淡漠外,NPI各项因子得分显著下降(P<0.05),NPI总分下降81.47%(P<0.05);照顾者的苦恼程度也随着患者精神行为症状的改善而降低;治疗前后患者的认知功能无显著性差异(P>0.05)。结论盐酸卡托普利可以明显改善AD痴呆患者的精神行为症状,但对患者的认知功能损害无明显疗效。     

Synthesis of inhibitors of the meso-diaminopimelate-adding enzyme from Escherichia coli

In order to obtain inhibitors of the meso-diaminopimelate-adding enzyme, which participates in the biosynthesis of bacterial peptidoglycan, several N^α -propionyl-dipeptides of the general formula Pr-l -Ala-ambo-Xaa-OH were synthesized. Xaa represented methionine S,S-dioxide, methionine S-oxide, methionine sulfoximine, and 2-amino-4-phosphonobutyric acid, i.e. transition state analogs of glutamine synthetase and γ-glutamyl-cysteine synthetase, which catalyze the same type of reaction as our target enzyme. After synthesis, the diastereoisomers were separated by preparative HPLC or t.l.c.; those containing methionine derivatives could be identified thanks to previously synthesized reference compounds. After preincubation with the meso-diaminopimelate-adding activity from Escherichia coli. the ld diastereoisomers displayed moderate inhibitory effects, whereas the ll ones were inefficient. The best inhibition was obtained with one diastereoisomer of Pr-l -Ala-ζ-2-amino-4-phosphonobutyrate, presumably the ld one. A chloromethylketone derivative Pr-l -Ala-d -Glu(CH₂Cl)-OH, potential affinity labeler of the meso-diaminopimelate-adding enzyme, was also synthesized. In the assay with preincubation, this compound behaved as the best inhibitor.     

Differential inhibitory effects of proton pump inhibitors on the metabolism and antiplatelet activities of clopidogrel and prasugrel

The interaction between proton pump inhibitors (PPIs) and clopidogrel/prasugrel was investigated. The IC50 values of omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole on the metabolic ratios of 2-oxo-clopidogrel/clopidogrel, H4 (the active metabolite of clopidogrel)/2-oxo-clopidogrel and R-138727 (the active metabolite of prasugrel)/prasugrel thiolactone in human liver microsomes were determined. The antiplatelet activities of clopidogrel and prasugrel were measured with or without PPIs. As a result, most PPIs (except for pantoprazole) inhibited the formation of 2-oxo-clopidogrel with IC50 values of 20-32 μm and inhibited the formation of H4 with IC50 values of 6-20 μm. PPIs inhibited the formation of R-138727 with IC50 values of 9-25 μm. Among the tested PPIs, omeprazole exhibited the highest inhibitory potency on the formation of H4. Omeprazole, esomeprazole and rabeprazole exhibited the highest inhibitory potencies on the formation of R-138727. For platelet aggregation, omeprazole and lansoprazole show higher inhibitory effects on the antiplatelet activity of clopidogrel. On the other hand, omeprazole, esomeprazole and rabeprazole significantly decreased the antiplatelet activity of prasugrel thiolactone. These data indicate that PPIs differ in their effects of inhibiting the metabolism and antiplatelet activities of clopidogrel and prasugrel.     

Effects of enzyme inducers and inhibitors on the pharmacokinetics of intravenous omeprazole in rats

A series of experiments using various inducers and inhibitors of the hepatic microsomal cytochrome P450 (CYP) isozymes were conducted to find CYP isozymes responsible for the metabolism of omeprazole in male Sprague-Dawley rats. Omeprazole, 20 mg/kg, was administered intravenously. In rats pretreated with SKF 525-A (a nonspecific CYP isozyme inhibitor in rats), the time-averaged nonrenal clearance (Cl(nr)) was significantly slower (77.1% decrease) than that in untreated rats. This indicated that omeprazole is metabolized via CYP isozymes in rats. Hence, rats were pretreated with various enzyme inducers and inhibitors. In rats pretreated with 3-methylcholanthrene and dexamethasone (main inducers of CYP1A1/2 and 3A1/2 in rats, respectively), the Cl(nr) values were significantly faster (43.8% and 26.3% increase, respectively). In rats pretreated with troleandomycin and quinine (main inhibitors of CYP3A1/2 and 2D1 in rats, respectively), the Cl(nr) values were significantly slower (20.9% and 12.9% decrease, respectively). However, the Cl(nr) values were not significantly different in rats pretreated with orphenadrine, isoniazid and sulfaphenazole (main inducers of CYP2B1/2 and 2E1, and a main inhibitor of 2C11, respectively, in rats) compared with those of respective control rats. The above data suggested that omeprazole could be mainly metabolized via CYP1A1/2, 3A1/2 and 2D1 in male rats.     

The quantitative determination of several inhibitors of the angiotensin-converting enzyme by CE

Capillary electrophoresis (CE) was applied to the study of several inhibitors of the angiotensin-converting enzyme. Separation of the compounds was performed by means of two phosphate buffers (each 100 mM) at pH 7.0 and 6.25, respectively [S. Hillaert, W. Van den Bossche, J. Chromatogr. A, 895 (2000) 33–42.]. Due to the highest selectivity of the first mentioned running buffer, the same system has been applied for the quantification of enalapril, lisinopril, quinapril, fosinopril, perindopril and benazepril in their corresponding pharmaceutical formulation. Especially, the possibility of simultaneous identification and quantification of the active ingredient in the finished product is very attractive. Excipients do not adversely affect the results. This paper deals with the validation of some parameters of the quantitative analysis: linearity, precision, accuracy and robustness.     

临床药师在冠心病监护病区促进血管紧张素转换酶抑制剂合理使用的成效

目的 提高血管紧张素转换酶抑制剂（ACEI）的使用合理性。方法 临床药师查阅2012年5月—2013年5月本院冠心病监护病区（CCU）所有病例,参照ACEI专家共识、指南以及药品说明书的标准对ACEI的使用合理性进行分析,但不予任何干预。2013年6月—2015年5月,临床药师参照同样标准,对ACEI的使用合理性进行干预。结果 对比干预前后的数据发现,ACEI使用百分比从80.1%提高至98.9%,ACEI起始剂量偏大的百分比由21.4%下降至0.9%,ACEI剂量不足的百分比从4.7%降至0.5%,差异均有统计学意义。结论 临床药师在促进ACEI的使用合理性方面可起主导作用。     

The effects of selected inhibitors of histone modifying enzyme on C6 glioma cells

BackgroundAberrant epigenetic histone modifications are implicated in cancer pathobiology, therefore histone modifying enzymes are emerging targets for anti-cancer therapy. There is a few evidence for deregulation of the histone modifying enzymes in glioblastomas. Glioma treatment is a clinical challenge due to its resistance to current therapies.MethodsThe effect of selected inhibitors on epigenetic modifications and viability of glioma C6 cells were studied using immunofluorescence and MTT metabolism test.ResultsWe found that VPA and TSA increase histone H4 acetylation in glioma cells, while chaetocin and BIX01294 at low concentrations reduce H3K9me3, and 3DZNep decreases H3K27me3. Long-term treatment with some epigenetic inhibitors affects viability of glioma cells.ConclusionsWe established the concentrations of selected inhibitors which in C6 glioma cells inhibit the enzyme activity, but do not decrease cell viability, hence allow to study the role of histone modifications in C6 glioma biology.     

血管紧张素转化酶抑制剂在冠心病治疗中的应用

本文以临床试验和中国2010年发表的《急性ST段抬高型心肌梗死诊断和治疗指南》、2012年发表的《非ST段抬高的急性冠脉综合征诊断和治疗指南》和2007年发表的《稳定型心绞痛诊断与治疗指南》为依据,从急性ST段抬高型心肌梗死、非ST段抬高的心肌梗死和稳定型心绞痛3个方面来概述血管紧张素转化酶抑制剂在冠心病治疗中的应用,同时通过一项调查研究给出此类药物在我国冠心病患者中的应用现况。     

酶抑制剂类抗糖尿病药物的分子水平筛选方法研究进展

酶抑制剂类抗糖尿病药物是目前药物研究的热点,而药物筛选技术是制约此类抗糖尿病新药研发速度的关键步骤。主要从分子水平总结近年来报道的与糖尿病相关的酶抑制剂类候选药物的筛选方法,包括传统方法和前沿方法,着重介绍极具潜力的毛细管电泳法、质谱法、生物传感法和微通道筛选方法等。     

The therapeutic potential of endothelin-1 receptor antagonists and endothelin-converting enzyme inhibitors on the cardiovascular system

Clinical trials have established bosentan, an orally active non-selective endothelin (ET) receptor antagonist, as a beneficial treatment in pulmonary hypertension. Trials have also shown short-term benefits of bosentan in systemic hypertension and congestive heart failure. However, bosentan also increased plasma levels of ET-1, probably by inhibiting the clearance of ET-1 by endothelin type B (ET_B) receptors, and this may mean its effectiveness is reduced with long-term clinical use. Preliminary data suggests that selective endothelin type A (ET_A) receptor antagonists (BQ-123, sitaxsentan) may be more beneficial than the non-selective ET receptor antagonists in heart failure, especially when the failure is associated with pulmonary hypertension. Experimental evidence in animal disease models suggests that non-selective ET or selective ET_A receptor antagonism may have a role in the treatment of atherosclerosis, restenosis, myocarditis, shock and portal hypertension. In animal models of myocardial infarction and/or reperfusion injury, non-selective ET or selective ET_A receptor antagonists have beneficial or detrimental effects depending on the conditions and agents used. Thus clinical trials of the non-selective ET or selective ET_A receptor antagonists in these conditions are not presently warranted. Several selective endothelin-converting enzyme inhibitors have been synthesised recently, and these are only beginning to be tested in animal models of cardiovascular disease, and thus the clinical potential of these inhibitors is still to be defined.     

有丝分裂关键激酶抑制剂的研究进展

目的综述有丝分裂关键激酶抑制剂近年来的研究进展。方法根据已报道的有丝分裂中关键激酶抑制剂的文献,将对有丝分裂过程中与肿瘤发生联系密切的激酶抑制剂,如Aurora激酶抑制剂、CDK(cyclin-dependent kinase)激酶抑制剂、PLK(Polo-like kinase)激酶抑制剂、CHK(check-point kinase)激酶抑制剂等目前的研究进展进行综述。结果有丝分裂关键激酶抑制剂已在临床前研究及临床研究中显示出很好的抗肿瘤活性。结论随着研究的不断深入,有丝分裂关键激酶抑制剂将在肿瘤治疗中发挥更大的作用。     

A comparison of the inhibitory effects of new non-tricyclic amine uptake inhibitors on the uptake of norepinephrine and 5-hydroxytryptamine into synaptosomes of the rat brain

The effects of new non-tricyclic amine uptake inhibitors, FS32 and FS97, on the uptake of [³H]-norepinephrine (NE) into the hypothalamic synaptosomes and [³H]-5-hydroxytryptamine (5-HT) into whole brain synaptosomes were studied. Their effects were compared with those of tricyclic antidepressants. The uptake of [³H]-NE was inhibited competitively by FS32 and FS97 with a respective K_i value of 6.5 × 10^?7 M and 3.8 × 10^?7 M. The potency of FS32 and FS97 to inhibit this uptake was almost comparable to that of clomipramine and imipramine, respectively. In the case of [³H]-5-HT uptake, FS32 and FS97 also showed competitive inhibition with a respective K_i value of 2.9 × 10^?6 M and 5.9 × 10^?6M. The ability of FS32 to inhibit [³H]-5-HT uptake was almost equal to that of nortriptyline, while FS97 was two times more potent than iprindole in inhibiting this uptake.     

A population-based study of the drug interaction between clopidogrel and angiotensin converting enzyme inhibitors

Aims

Clopidogrel and angiotensin converting enzyme (ACE) inhibitors are commonly co-prescribed drugs. Clopidogrel inhibits carboxylesterase 1 (CES1), the enzyme responsible for converting prodrug ACE inhibitors (such as ramipril and perindopril) to their active metabolites. The clinical implications of this potential drug interaction are unknown. The clinical consequences of the potential drug interaction between clopidogrel and prodrug ACE inhibitors were examined.

Methods

We conducted a nested case–control study of Ontarians aged 66 years and older treated with clopidogrel between September 1 2003 and March 31 2013 following acute myocardial infarction. Cases were subjects who died or were hospitalized for reinfarction or heart failure in the subsequent year, and each was matched with up to four controls. The primary outcome was a composite of reinfarction, heart failure or death. The primary analysis examined whether use of the prodrug ACE inhibitors ramipril or perindopril was more common among cases than use of lisinopril, an active ACE inhibitor.

Results

Among 45 918 patients treated with clopidogrel following myocardial infarction, we identified 4203 cases and 14 964 controls. After adjustment, we found no association between the composite outcome and use of perindopril (adjusted odds ratio (aOR) 0.94, 95% confidence interval (CI) 0.76, 1.16) or ramipril (aOR 0.97, 95% CI 0.80, 1.18), relative to lisinopril. Secondary analyses of each element of the composite outcome yielded similar findings.

Conclusions

Following myocardial infarction, use of clopidogrel with ACE inhibitors activated by CES1 is not associated with an increased risk of adverse cardiovascular outcomes relative to lisinopril. These findings suggest that the recently described drug interaction between clopidogrel and prodrug ACE inhibitors is of little clinical relevance.     

Novel approaches to the development of tyrosine kinase inhibitors and their role in the fight against cancer

Introduction: Protein tyrosine kinase inhibitors are currently one of the most important classes of cancer drugs and one of the most impressive approaches of targeted cancer therapy. Aberrant activation of tyrosine kinase pathways is among the most dysregulated molecular pathways in human cancers; therefore, a large number of tyrosine kinases may serve as valuable molecular targets. To date, several inhibitors of tyrosine kinases have been approved and there are hundreds more compounds that are in various stages of development. Because of the deregulation in human malignancies, the ABL1, SRC, the epidermal growth factor receptor and the vascular endothelial growth factor receptor kinases are among the protein kinases that are considered as prime molecular targets for selective inhibition.

Areas covered: This review focuses on most important small-molecule inhibitors that serve as a model for future development. They also provide a broad overview of some of the new approaches and challenges in the field.

Expert opinion: With the exception of a few malignancies seemingly driven by a limited number of genetic lesions, current targeted therapeutic approaches have shown only limited efficacy in advanced cancers. Consequently, more sophisticated strategies, such as identification of pathogenic ‘driver' mutations and optimization of personalized therapies are needed.     

Clinical trials evaluating angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in the setting of acute myocardial infarction

There is strong evidence from controlled clinical trials that in the setting of acute myocardial infarction complicated by heart failure or isolated left ventricular dysfunction, angiotensin-converting enzyme inhibitors started late during hospitalisation and continued in the long term, significantly reduced mortality and improved the prognosis. On the other hand, administration of angiotensin-converting enzyme inhibitors during the first 24 h in unselected patients with acute myocardial infarction provided only a slight benefit in terms of mortality. Angiotensin-II receptor blockers have and are being examined in the setting of acute myocardial infarction with left ventricular dysfunction and can provide an alternative for patients who cannot tolerate angiotensin-converting enzyme inhibitors. In this article, an evidence-based review of these major trials and suggestions for clinical application are presented.     

血管紧张素转换酶抑制剂的临床应用进展

就近年来血管紧张素转换酶抑制剂(ACEI)在临床应用、不良反应、费用-效益分析方面的进展进行了综述，并进行讨论，表明ACEI具有广泛的应用。