Burger's Medicinal Chemistry and Drug Discovery最新文献

{"title":"Tetracycline, Aminoglycoside, Macrolide, and Miscellaneous Antibiotics","authors":"L. Mitscher","doi":"10.1002/0471266949.BMC088.PUB2","DOIUrl":"https://doi.org/10.1002/0471266949.BMC088.PUB2","url":null,"abstract":"The identity, chemistry, biosynthesis, antimicrobial spectra, molecular mode of action, bacterial resistance mechanisms, side effects, and clinical uses of these important chemotherapeutic agents are discussed. \u0000 \u0000 \u0000Keywords: \u0000 \u0000antibiotics; \u0000aminoglycoside; \u0000macrolide; \u0000miscellaneous; \u0000tetracycline","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"13 1","pages":"403-480"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77149454","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}

{"title":"Drug Discovery in Non‐Life‐Threatening Disorders: Erectile Dysfunction, Insomnia, and Smoking Cessation","authors":"D. Rotella","doi":"10.1002/0471266949.BMC200","DOIUrl":"https://doi.org/10.1002/0471266949.BMC200","url":null,"abstract":"Drug discovery for non-life-threatening disorders is an active area of medicinal chemistry research. This chapter will describe the discovery and properties of phosphodiesterase 5 inhibitors for erectile dysfunction, the medicinal chemistry of agents for treatment of insomnia, and smoking cessation. \u0000 \u0000 \u0000Keywords: \u0000 \u0000insomnia; \u0000phosphodiesterase 5 inhibitors; \u0000smoking cessation","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"126 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73573418","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}

{"title":"Natural Products as Cytotoxic Agents","authors":"S. Cutler, H. Cutler","doi":"10.1002/0471266949.BMC216","DOIUrl":"https://doi.org/10.1002/0471266949.BMC216","url":null,"abstract":"In the first decade of the twenty-first century, the occurrence of cancers has increased not only in First World countries but also in those countries considered to have a lower standard of living, according to a world cancer report issued in 2008 for the IARC Nonserial Publication by Boyle and Levin. So widespread is cancer, in its various forms, that most adults have either had family members or had friends who have been afflicted by the disease. Projected figures for cancers indicate, in the aforementioned publication, that 12 million cancer cases were diagnosed in 2008 alone and that the number of cancer victims has doubled since 1978. Coupled to the psychological impact that a diagnosis has on an individual is the cost of treatment that must also be considered. Again, according to the National Cancer Institute (December 2008) these costs are estimated to be US$147 billion by 2020. An article, published in USA Today, claims that new cancer cases in 2008 were projected to be 40,480. And the cost for elderly Medicare patients will be US$21.1 billion for 5 years of treatment for the period 2004–2009. Sadly, one in eight patients with advanced stages of cancer will turn down the offer of recommended care because of costs. While cases may have been misdiagnosed in the twentieth century, the sophisticated techniques available today give a clearer graph of the incidence of the disease. With advanced diagnostics, there has been a concomitant advance in anticancer chemotherapy. \u0000 \u0000 \u0000Keywords: \u0000 \u0000cancer; \u0000cytotoxic agents; \u0000DNA; \u0000therapeutic agents","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"6 1","pages":"1-48"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80219108","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}

{"title":"The Role of Permeability in Drug ADME/PK, Interactions and Toxicity, and the Permeability‐Based Classification System (PCS)","authors":"U. Fagerholm","doi":"10.1002/0471266949.BMC163","DOIUrl":"https://doi.org/10.1002/0471266949.BMC163","url":null,"abstract":"Permeability (Pe) is one of the key determinants in the absorption, distribution, metabolism, excretion/pharmacokinetics (ADME/PK) of drugs and their metabolites. Predictions of ADME/PK, interactions, elimination routes, exposures, and toxicity require, therefore, that the role of permeability in different organs is considered, investigated and understood. That includes studies of and knowledge about the relation between Pe and fraction absorbed (fa) (or fraction reabsorbed; fra) in various organs, and the interplay between passive permeability and active permeability, metabolism and solubility/dissolution. Relationships between passive Pe and fa in the human intestine, liver, renal tubuli (fra), and brain have been established, and these are the basis of the Permeability-Based Classification System (PCS). This system demonstrates sigmoidal Pe versus fa and fra relationships of different shapes and shifts, and is divided into four permeability categories (very high/high/intermediate/low). Results show or indicate that the liver and brain have comparably high intrinsic passive uptake capacities, metabolism (rather than uptake, diffusion, and dissociation) is the general rate-limiting step in hepatic metabolic clearance (CLH), and few high permeability compounds have dissolution-limited gastrointestinal fa. Active transport processes contribute to the intestinal and hepatic uptake, and renal, biliary, and intestinal drug excretion, of many drugs with limited passive Pe. Active transport could be clinically relevant for brain uptake of both low and high passive permeability compounds. Related drug–drug interactions and polymorphism appear most pronounced for drugs actively absorbed and excreted by the liver. Combined with intrinsic metabolic CL data, the PCS is useful for predictions of CLH, renal and biliary excretion potential, gut-wall extraction ratio, oral bioavailability and effects of polymorphism, and for assessment of potential drug–drug or drug–metabolite interactions, and drug and metabolite organ/cell trapping. \u0000 \u0000 \u0000Keywords: \u0000 \u0000absorption; \u0000classification system; \u0000clearance; \u0000excretion; \u0000interaction; \u0000metabolism; \u0000permeability; \u0000pharmacokinetics; \u0000prediction; \u0000toxicity","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84023457","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}

{"title":"Diabetes Drugs: Present and Emerging","authors":"J. Tilley, J. Grimsby, S. Erickson, Berthel Steven Joseph","doi":"10.1002/0471266949.BMC198","DOIUrl":"https://doi.org/10.1002/0471266949.BMC198","url":null,"abstract":"This chapter includes a summary of the mechanism of action, history, and ADME properties compounds selected from four classes of marketed drugs for the treatment of type 2 diabetes. These include the biguanides (metformin), α-glucosylase inhibitors, sulfonylureas, and glinides. In addition, a discussion of several advanced, emerging classes of drugs together with lead structures is provided. The mechanistic classes of emerging drugs include inhibitors of the sodium glucose cotransporter 2 (SGLT2), glucokinase activators (GKAs), inhibitors of fructose-1,6-bisphosphatase (FPase), inhibitors of 11-β-sterol dehydrogenase (11-β-HSD1), agonists acting on the G-coupled-protein receptor GPR119, and mimics of the sirtuin family member SIRT1. \u0000 \u0000 \u0000Keywords: \u0000 \u0000diabetes; \u0000glucokinase; \u0000metformin; \u0000sodium glucose cotransporter; \u0000salfonyl urea","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"16 1","pages":"1-38"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90920064","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}

{"title":"Process Development of Protein Therapeutics","authors":"James N. Thomas, S. Guhan, D. Pettit","doi":"10.1002/0471266949.BMC160","DOIUrl":"https://doi.org/10.1002/0471266949.BMC160","url":null,"abstract":"The application of recombinant DNA technology to the production of protein therapeutics has undergone considerable progress since first introduced 30 years ago. Considerable scientific effort has been devoted to developing robust processes that produce large amounts of complex proteins with the desired product quality attributes. An overview of the contributions from the four major disciplines working in concert to deliver these processes and methods will be covered. This chapter will discuss some of the tools, methods, and approaches used to produce, purify, formulate, and analyze the drugs of modern biotechnology. Future trends in each of the disciplines will also be presented. \u0000 \u0000 \u0000Keywords: \u0000 \u0000cell culture; \u0000expression systems; \u0000gene amplification; \u0000transfection; \u0000vectors","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"31 1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87550036","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}

{"title":"Recent Trends in Structure‐Based Drug Design and Energetics","authors":"A. Andricopulo, R. Guido, D. Trivella, I. Polikarpov, A. Leitão, C. Montanari","doi":"10.1002/0471266949.BMC141","DOIUrl":"https://doi.org/10.1002/0471266949.BMC141","url":null,"abstract":"The integration of cheminformatics tools, thermodynamic data, and structural information play a major role in the drug discovery process. Altogether, these methods can describe the molecular forces that govern the affinity and selectivity of bioactive molecules for their macromolecular targets. By being able to uncover the relationships between structure and energetics when using high-resolution structural information and modern biophysical methods, one can fulfill the challenge of correctly interpreting drug–macromolecular interactions. These interactions are prone to be unveiled and scrutinized when structure-based drug design is applied to a known three-dimensional (3D) structure of a given protein. If fully integrated with structure-based ligand design in an iterative way, computational methods can be of invaluable help to describe the ligand–target (cocomplex) formation. Structure-based virtual screening can be used to rapid cherry-pick the best candidates from a large pool of compounds in a chemical library after docking into the active sites of 3D protein structures. To pursue this, the quantification of favorable and unfavorable interactions requires knowledge of the thermodynamics of the interactions. Docking algorithms and molecular dynamics simulations can be used to predict binding energies for positioning ligands in target binding sites, but they only provide information regarded to the prediction of the change in the Gibbs free energy change, which hampers the thoroughly dissection of all other very important thermodynamic parameters—enthalpy, entropy, and heat capacity change. The major goal of this chapter is to show the integration of structure-based drug design with the energetic. Microcalorimetric measurement of the drug–macromolecular interaction is an effective way to enhance the power, the medicinal chemists have on hand, to pursue a knowledge-based approach toward the description of all of the noncovalent bond terms that take place in the cocomplex formation. \u0000 \u0000 \u0000Keywords: \u0000 \u0000structure-based virtual screening; \u0000isothermal titration calorimetry; \u0000drug–macromolecular interaction energetics, nuclear receptors; \u0000transthyretin amyloidosis inhibitors","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"45 1","pages":"685-724"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81049623","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}

{"title":"Recent Advances in Hepatitis C Therapies","authors":"B. Jonathan, Z. Christoph, L. Jeremy, F. Michael","doi":"10.1002/0471266949.BMC238","DOIUrl":"https://doi.org/10.1002/0471266949.BMC238","url":null,"abstract":"First page of article \u0000 \u0000 \u0000Keywords: \u0000 \u0000anti-HCV agents; \u0000hepatitis C virus; \u0000STAT-C therapies","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"216 1","pages":"169-218"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75561989","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}

{"title":"Combinatorial Chemistry and Multiple Parallel Synthesis","authors":"L. Mitscher, J. Aubé, Apurba Dutta, Jennifer E. Golden","doi":"10.1002/0471266949.BMC019.PUB2","DOIUrl":"https://doi.org/10.1002/0471266949.BMC019.PUB2","url":null,"abstract":"The current state of the art in drug seeking through applications of combinatorial chemical and multiple parallel synthetic methods is reviewed with examples culled from the contemporaneous literature. \u0000 \u0000 \u0000Keywords: \u0000 \u0000combinatorial chemistry; \u0000drug seeking; \u0000multiple parallel synthesis","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"1 1","pages":"275-368"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76545712","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}

{"title":"ADMET In Vitro Profiling: Utility and Applications in Lead Discovery","authors":"E. Kerns, L. Di, G. Carter","doi":"10.1002/0471266949.BMC118","DOIUrl":"https://doi.org/10.1002/0471266949.BMC118","url":null,"abstract":"ADMET properties are a vital integral part of drug discovery because they determine the pharmacokinetics and safety of clinical development candidates. Diverse ADMET profiling assays have been developed and implemented to provide property data for drug discovery team decision making. Their utility and applications in lead discovery include the following: lead selection, diagnosis of poor PK, guidance for structure modification, solving specific project team property issues, providing accurate biological data for SAR, selecting compounds for in vivo PK and PD studies, and improving dosing for optimum exposure in vivo. ADMET properties are discussed along with case studies and assays. \u0000 \u0000 \u0000Keywords: \u0000 \u0000absorption; \u0000ADMET; \u0000assays; \u0000blood–brain barrier; \u0000bioassay; \u0000Caco-2; \u0000cytochrome P450 (CYP); \u0000distribution; \u0000drug–drug interaction; \u0000drug-like properties; \u0000excretion; \u0000hERG blocking; \u0000in vitro assay; \u0000lipophilicity; \u0000metabolism; \u0000optimization; \u0000PAMPA; \u0000permeability; \u0000pharmacokinetics; \u0000physicochemical; \u0000pKa; \u0000protein binding; \u0000rule of five; \u0000stability; \u0000solubility; \u0000toxicity; \u0000transporters","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"24 1","pages":"47-72"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91543205","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}