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Current opinion in drug discovery & development最新文献

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Pictet-Spengler reactions for the synthesis of pharmaceutically relevant heterocycles. 合成药学上相关杂环的Pictet-Spengler反应。
Current opinion in drug discovery & development Pub Date : 2010-01-01
Karolina Pulka
{"title":"Pictet-Spengler reactions for the synthesis of pharmaceutically relevant heterocycles.","authors":"Karolina Pulka","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The synthesis of biologically active heterocyclic scaffolds is one of the significant challenges of modern synthetic chemistry. The Pictet-Spengler (PS) reaction, known for approximately a century, remains a particularly popular cyclization method. This review describes recent applications of the PS reaction in the total synthesis of alkaloids and biologically active analogs of tetrahydroisoquinoline and tetrahydro-β-carboline. The utility of PS cyclization in the synthesis of a range of heterocyclic scaffolds is also described.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29455833","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: 0
Homogenous asymmetric hydrogenation: Recent trends and industrial applications. 均相不对称氢化:最新趋势和工业应用。
Current opinion in drug discovery & development Pub Date : 2010-01-01
Andreas M Palmer, Antonio Zanotti-Gerosa
{"title":"Homogenous asymmetric hydrogenation: Recent trends and industrial applications.","authors":"Andreas M Palmer,&nbsp;Antonio Zanotti-Gerosa","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Recent advances in the field of homogeneous asymmetric hydrogenation are presented in this review. An analysis of academic literature published in the past 2 years highlights significant advances in the asymmetric hydrogenation of functional groups that previously were considered difficult to hydrogenate, as well as the emergence of novel concepts in catalysis, such as the use of non-traditional metals, phosphine-free catalysts and chiral counterions. An analysis of industry publications from 2009 and 2010 highlights more established applications of asymmetric hydrogenation reactions; these are discussed with a particular focus on practical aspects, such as catalyst selection, experimental conditions and the removal of metal residues.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29455835","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: 0
Cytochrome P450 proteins: retention and distribution from the endoplasmic reticulum. 细胞色素P450蛋白:内质网的保留和分布。
Current opinion in drug discovery & development Pub Date : 2010-01-01
Etienne P A Neve, Magnus Ingelman-Sundberg
{"title":"Cytochrome P450 proteins: retention and distribution from the endoplasmic reticulum.","authors":"Etienne P A Neve,&nbsp;Magnus Ingelman-Sundberg","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Cytochrome P450 (CYP) is a large family of well-conserved integral membrane proteins localized primarily in the membrane of the endoplasmic reticulum (ER), where these enzymes metabolize a variety of both endogenous and exogenous compounds. It has become apparent that these microsomal CYP proteins are also present in other cellular compartments, such as the cell surface and in mitochondria, where the enzymes display catalytic activity toward CYP-specific substrates, in some cases with altered substrate specificity. CYP-drug adducts exposed at the cell surface are important mediators of idiosyncratic drug toxicities. Therefore, understanding the molecular mechanisms responsible for directing these microsomal CYPs to other, non-ER cellular compartments is important. These alternatively localized CYPs should be considered as possible drug targets and as important factors during drug discovery and development, as the detoxification capacity is lower in the compartments where such CYP proteins are located. This review discusses the mechanisms of intracellular CYP transport, and the implications of the presence of CYP proteins in extra-ER compartments for drug metabolism and toxicity.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28624970","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: 0
Recent advances in the understanding of drug-mediated infusion reactions and cytokine release syndrome. 药物介导的输液反应和细胞因子释放综合征的最新研究进展。
Current opinion in drug discovery & development Pub Date : 2010-01-01
Mindi Walker, Dorie Makropoulos, Ram Achuthanandam, Peter J Bugelski
{"title":"Recent advances in the understanding of drug-mediated infusion reactions and cytokine release syndrome.","authors":"Mindi Walker,&nbsp;Dorie Makropoulos,&nbsp;Ram Achuthanandam,&nbsp;Peter J Bugelski","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Infusion reactions and cytokine release syndrome (CRS) are an emerging issue in drug development and are of particular importance with the development of new therapeutic proteins. Increasing concerns regarding patient safety require a better understanding of the mechanism involved and the development of novel methods for preventing and predicting such reactions and CRS. This review discusses developments during the past few years in understanding the mechanisms that cause infusion reactions and CRS, advances in approaches to prevent CRS, the reason why preclinical animal models are unreliable predictors of CRS, and new developments in the design and analysis of in vitro screening systems for the prediction of CRS.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28624976","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: 0
Challenges in the prediction and modeling of oral absorption and bioavailability. 口服吸收和生物利用度预测和建模的挑战。
Current opinion in drug discovery & development Pub Date : 2010-01-01
Paul D Metcalfe, Simon Thomas
{"title":"Challenges in the prediction and modeling of oral absorption and bioavailability.","authors":"Paul D Metcalfe,&nbsp;Simon Thomas","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>To predict the performance of a drug following oral dosing, a thorough understanding of the dissolution, uptake and metabolism of the compound is required. In this review, approaches to in silico modeling of these processes are discussed. Although oral absorption, which is limited by dissolution and passive permeation, is to some extent predictable, bioavailability, which is influenced by first-pass metabolism in the intestines and liver, is much more difficult to predict. Much of the difficulty in predicting oral absorption and bioavailability is in the experimental quantification of solubility in the gastrointestinal tract lumen, membrane permeability, plasma protein binding, metabolism and active transport, rather than the formulating of the mathematical models.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28624974","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: 0
Using more environmentally friendly solvents and benign catalysts in performing conventional organic reactions. 使用更环保的溶剂和良性催化剂进行传统的有机反应。
Current opinion in drug discovery & development Pub Date : 2010-01-01
Brindaban C Ranu, Amit Saha, Raju Dey
{"title":"Using more environmentally friendly solvents and benign catalysts in performing conventional organic reactions.","authors":"Brindaban C Ranu,&nbsp;Amit Saha,&nbsp;Raju Dey","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The protection of the environment from toxic materials is an area of increasing concern. This review describes selected chemical processes that use more environmentally friendly solvents and less toxic catalysts. For example, water, ionic liquids and supercritical fluids have demonstrated promising activity as alternative benign reaction media for various reactions. The advantages of neat reactions in the absence of any solvent and the use of fluorous compounds as phase-separable catalysts are also described.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29455832","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: 0
The role of metabolites in predicting drug-drug interactions: focus on irreversible cytochrome P450 inhibition. 代谢物在预测药物-药物相互作用中的作用:关注不可逆的细胞色素P450抑制。
Current opinion in drug discovery & development Pub Date : 2010-01-01
Brooke M VandenBrink, Nina Isoherranen
{"title":"The role of metabolites in predicting drug-drug interactions: focus on irreversible cytochrome P450 inhibition.","authors":"Brooke M VandenBrink,&nbsp;Nina Isoherranen","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The irreversible inhibition of cytochrome P450 (CYP) enzymes can cause significant drug-drug interactions (DDIs). The formation of metabolites is fundamental for the inactivation of CYP enzymes. Of the 19 CYP enzyme inactivators for which the mechanism of action has been established, 10 have circulating metabolites, which are on the metabolic pathway to inactivation of the CYP enzyme. Because inactivation of CYP enzymes usually requires multiple metabolic steps, the prediction of interactions between metabolites and CYPs in vivo may require complex models and the availability of data generated in vitro from each metabolite. Data discussed in this review suggest that circulating metabolites are more important in CYP inhibition in vivo than has been acknowledged.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2898504/pdf/nihms210883.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28624971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Roles of CD44 in chemical-induced liver injury. CD44在化学性肝损伤中的作用。
Current opinion in drug discovery & development Pub Date : 2010-01-01
Kiminori Kimura, Seishu Hayashi, Masahito Nagaki
{"title":"Roles of CD44 in chemical-induced liver injury.","authors":"Kiminori Kimura,&nbsp;Seishu Hayashi,&nbsp;Masahito Nagaki","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>CD44 has been identified as one of the adhesion molecules that regulate cell migration in inflamed tissue. The principal ligand of CD44 is hyaluronan, and CD44 is involved in the metabolism of this compound. Furthermore, an increasing quantity of evidence suggests that CD44 has various functions related to inflammatory disease. This review focuses on the potential roles of CD44 in the pathogenesis of chemical-induced liver injury and discusses some of the functions of this protein in pathological processes. The discovery that CD44 deficiency induces severe liver injury, (associated with an increase in hepatocyte apoptosis) rather than suppressing liver inflammation is summarized. These data suggest that targeted therapies against adhesion molecules should be monitored carefully to ensure that liver disease is not exacerbated by treatment.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28624973","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: 0
Highly reactive 4-membered ring nitrogen-containing heterocycles: Synthesis and properties. 高活性四元环含氮杂环:合成与性质。
Current opinion in drug discovery & development Pub Date : 2010-01-01
Benito Alcaide, Pedro Almendros, Cristina Aragoncillo
{"title":"Highly reactive 4-membered ring nitrogen-containing heterocycles: Synthesis and properties.","authors":"Benito Alcaide,&nbsp;Pedro Almendros,&nbsp;Cristina Aragoncillo","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>4-Membered nitrogen-containing heterocycles, such as β-lactams (ie, 2-azetidinones) and azetidines, are useful substrates in organic chemistry for the design and preparation of biologically active compounds by functionalization of the different positions of the ring. In addition, these compounds are versatile building blocks for the synthesis of other types of nitrogen-containing compounds with potential biological properties. This review summarizes recent data regarding the preparation and properties of 4-membered nitrogen-containing heterocyclic rings, as well as their biological activities.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29455834","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: 0
Enantioselective synthesis of substituted oxindoles and spirooxindoles with applications in drug discovery. 取代吲哚和螺旋吲哚的对映选择性合成及其在药物发现中的应用。
Current opinion in drug discovery & development Pub Date : 2010-01-01
Joseph J Badillo, Nadine V Hanhan, Annaliese K Franz
{"title":"Enantioselective synthesis of substituted oxindoles and spirooxindoles with applications in drug discovery.","authors":"Joseph J Badillo,&nbsp;Nadine V Hanhan,&nbsp;Annaliese K Franz","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>This review describes recent methods for the enantioselective synthesis of oxindoles and spirooxindoles, with a particular focus on scaffolds with applications in drug discovery. The synthetic challenge of the spiro-motif and the important biological activity of spirooxindoles continue to encourage the development of creative methods to access these important structures. Unique spirocycles often result from creative synthetic methods that would not typically be identified using classical synthetic disconnections. To establish the importance of asymmetric synthesis in the context of oxindole structures, recent examples are highlighted in which stereospecific binding and differential biological activity have been demonstrated based on the configuration at the 3-position. This review is organized by type of catalyst and synthetic strategy in order to compare traditional organometallic and Lewis acid methods with more recent organocatalytic methods. A section describing multicomponent and cascade reaction strategies is also included.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29455774","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: 0
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