Burger's Medicinal Chemistry and Drug Discovery最新文献

{"title":"Antiprotozoal/Antiparasitic Agents","authors":"P. Woster","doi":"10.1002/0471266949.BMC235","DOIUrl":"https://doi.org/10.1002/0471266949.BMC235","url":null,"abstract":"Collectively, diseases caused by parasitic protozoa, including human African trypanosomiasis (HAT), Chagas' disease and leishmaniasis, threaten more than 550 million people worldwide and cause nearly 150,000 deaths annually. The causative organisms for these diseases are unicellular trypanosomatid parasites of the genera Trypanosoma brucei, Trypanosoma cruzi, and Leishmania sp., respectively. Drug therapies available for these diseases have not changed significantly in the past 50 years, and currently used agents are far less than satisfactory due to extreme toxicity, and because resistant parasitic strains are becoming more prevalent. These diseases are confined to impoverished or rural areas of Mexico, Central America, South America, sub-Saharan Africa, the Middle East, Indonesia, and India. As such, drug discovery efforts against trypanosomatid diseases are limited because patients in underdeveloped areas cannot afford therapy, and because the infected population is too small to justify the required research expenditures. In addition, antiparasitic research in Third World nations is often hampered by economic issues and political turmoil, virtually assuring that the world's most impoverished people will continue to bear the major burden of parasitic disease. Clearly, there is a need for new anti-infective agents that are potent, nontoxic and inexpensive to manufacture. In this chapter, the etiology of these diseases and their current treatment are described. The chapter also deals with medicinal chemistry aspects of efforts to identify new drug targets for parasitic diseases, and to produce novel inhibitors of trypanosomatid growth for use as antiparasitic agents. \u0000 \u0000 \u0000Keywords: \u0000 \u0000amidine; \u0000antiparasitic; \u0000Chaga's disease; \u0000chemotherapy; \u0000cutaneous leishmaniasis; \u0000cysteine protease; \u0000glucose metabolism; \u0000glucose transport; \u0000glycosome; \u0000guanidine; \u0000human African trypanosomiasis; \u0000Leishmania donovani; \u0000life cycle; \u0000lipid metabolism; \u0000nucleotide transporter; \u0000polyamines; \u0000protozoa; \u0000Trypanosoma brucei; \u0000Trypanosoma cruzi; \u0000visceral leishmaniasis","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"33 1","pages":"563-600"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86811167","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":"Use of Biological Fingerprints Versus Structure/Chemotypes to Describe Molecules","authors":"J. Mason","doi":"10.1002/0471266949.BMC151","DOIUrl":"https://doi.org/10.1002/0471266949.BMC151","url":null,"abstract":"Molecules are usually described by their chemical structure and by fingerprints derived from this. These range from 2D structure based, that only represent the underlying structure that gives rise to the properties recognized by a biological target to 3D pharmacophores or molecular interaction fields, that much better represent how the protein binding sites would “see” a molecule. However, all of these have many limitations, including conformation for the 3D structure-based approaches. More recently, experimental profiling data have been generated that enables a molecule to be described by a fingerprint of binding affinity to a diverse set of biological targets (pharmacological and “antitargets” such as CYP450 metabolic enzymes). These results show that small changes in structure can cause large changes in broad biological profile, and that a structure-based analysis/clustering of compounds, such as different hits, leads, or clinical candidates, often does not provide a differentiation that is relevant in biological space. The data show that “selective” versus “nonselective” compounds, and the type of off-target effects are not evident from a “chemotype” approach. The concept of “biological fingerprints” as a better way to describe compounds of biological interest is described in this chapter, focusing on the power of these descriptors versus structure-based descriptors to differentiate compounds and enable the selection of the best lead compounds.Keywords:biological profiling;chemotype;drug design;fingerprints;pharmacological profiling;pharmacophore;selectivity","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"10 1","pages":"481-504"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82006093","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":"Synthetic DNA-Targeted Chemotherapeutic Agents And Related Tumor-Activated Prodrugs","authors":"W. Denny","doi":"10.1002/0471266949.BMC075.PUB2","DOIUrl":"https://doi.org/10.1002/0471266949.BMC075.PUB2","url":null,"abstract":"Synthetic drugs have always played an important role in cancer therapy. The first systemic anticancer drugs were synthetic DNA alkylating agents and DNA antimetabolites. The original antimetabolites such as cytosine arabinoside and 5-fluorouracil have been augmented by more recent compounds such as gemcitabine, fludarabine, cladribine, and pentostatin, which inhibit DNA polymerase action during DNA synthesis. A new development is the related compounds deazacytidine and decitabine, which inhibit reactivate silenced genes by inhibition of cytosine methylation. Nitrogen mustards, platinum complexes, nitrosoureas, and triazene-based DNA-methylating agents are direct DNA-modifying agents that still play an important role in clinical treatment. Methotrexate and more recent lipophilic analogs, together with older drugs such as 5-fluorouracil, are used as inhibitors of different enzymes in the folate pathway necessary for the synthesis of pyrimidine nucleotides. The potent activity of natural products such as doxorubicin also led to the development of the synthetic topoisomerase inhibitors that are now another important group of drugs whose therapeutic effects are due to enzyme-mediated DNA modification. Finally, an increasing understanding of tumor physiology and genetics has allowed the development of tumor-activated prodrugs of DNA-active agents. Using hypoxia, gene therapy or antibody targeting to activate such prodrugs specifically in tumor tissue has the potential to increase the therapeutic index of these agents by limiting the exposure of sensitive nontumor cell populations. \u0000 \u0000 \u0000Keywords: \u0000 \u0000alkylating agent; \u0000antibody; \u0000antifolate; \u0000antimetabolite; \u0000DNA intercalator; \u0000gene therapy; \u0000hypoxia; \u0000mustard; \u0000nitrosourea; \u0000platinum complex; \u0000topoisomerase inhibitor; \u0000triazene; \u0000tumor-activated prodrug","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"34 3 1","pages":"83-150"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90454537","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":"β-Lactam Antibiotics","authors":"S. Testero, J. Fisher, S. Mobashery","doi":"10.1002/0471266949.BMC226","DOIUrl":"https://doi.org/10.1002/0471266949.BMC226","url":null,"abstract":"The β-lactam classes of antibacterials are preeminent in the treatment of bacterial infection due to their unparalleled clinical efficacy and clinical safety. Following the discovery of the penicillins, successive β-lactam drug discovery has added the cephalosporin, penem cephamycin, clavulanate, monobactam, nocardicin, and carbapenem subclasses. The driving force behind much of this era of discovery is the staggering ability of pathogenic bacteria to adapt previous generations of the β-lactam by the acquisition and expression of resistance mechanisms. Although many factors contribute to β-lactam resistance, alterations to the molecular targets of the β-lactams (the penicillin binding proteins) and the use of enzymes (the β-lactamases) capable of the hydrolytic deactivation of the β-lactams are paramount. This review traces the historical development of β-lactam drug discovery, with emphasis on the most recent progress in the medicinal chemistry, biochemistry, and microbiology of the β-lactams leading to the discovery of new generation β-lactam antibacterials effective against the Gram-negative and -positive bacterial pathogens of current medical concern. \u0000 \u0000 \u0000Keywords: \u0000 \u0000β-lactam; \u0000β-lactamase; \u0000penicillin; \u0000cephalosporin; \u0000monobactam","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"30 1","pages":"257-402"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78162537","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":"New Strategies for Natural Products Lead Generation","authors":"G. Carter, V. Bernan, F. Koehn","doi":"10.1002/0471266949.BMC116","DOIUrl":"https://doi.org/10.1002/0471266949.BMC116","url":null,"abstract":"Microbial sources of natural products are increasingly valued for their chemical diversity and access to biosynthetic pathways. It appears that an incredible repository of untapped microbial life and associated chemical diversity remain to be exploited. Molecular techniques such as “metagenomics” are beginning to provide access to cryptic biosynthetic pathways, which are also revealing new chemistry. Refined libraries of natural products with well-characterized components provide enhanced value as screening sources. These libraries continue to provide new chemical entities that inform biological processes and provide leads for therapeutic agents. There is a renaissance of phenotypic screening that promises to uncover numerous new links between secondary metabolites and their roles in biology. Genomic methods are growing in value as our understanding of biosynthetic processes at the molecular level expands. Screening of DNA sequences for pathways that yield particular chemistries is now a reality for certain types of biosynthetic processes, especially type I polyketide synthases and nonribosomally produced peptides. \u0000 \u0000 \u0000Keywords: \u0000 \u0000biodiversity; \u0000marine actinomycetes; \u0000microbial genomics; \u0000natural products lead generation; \u0000natural products libraries; \u0000screening; \u0000secondary metabolites","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"81 1","pages":"191-220"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73039116","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":"CCR5 Antagonists: Small‐Molecule Inhibitors For Blocking HIV‐1 Entry","authors":"J. Tagat","doi":"10.1002/0471266949.BMC230","DOIUrl":"https://doi.org/10.1002/0471266949.BMC230","url":null,"abstract":"First page of article \u0000 \u0000 \u0000Keywords: \u0000 \u0000CCR5 antagonists; \u0000blocking HIV-1 entry; \u0000small-molecule inhibitors","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"56 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83940523","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":"Immunosuppressive Agents for the Prevention of Transplantation Rejection","authors":"W. Pitts","doi":"10.1002/0471266949.BMC206","DOIUrl":"https://doi.org/10.1002/0471266949.BMC206","url":null,"abstract":"This chapter will focus on “small” molecule therapeutics that demonstrate useful immunosuppressant activity including established classes such as calcineurin inhibitors (cyclosporin A and tacrolimus), mTOR (mammalian target of rapamycin) agents (sirolimus, everolimus), and antiproliferative/antimetabolite agents (azathioprine, mycophenolic acid derivatives). This chapter will also introduce some agents with newer pharmacology mechanisms such as sphingosine receptor modulation (FTY720), inhibition of JAK3 (CP-690,550), and inhibition of PKC θ (AEB071). Other agents useful in organ transplantation including glucocorticoids (such as prednisone and dexamethasone), nitrogen mustards (such as cyclophosphamide), and biologic agents (such as muromonab-CD3, basiliximab, and daclizumab) are discussed elsewhere. \u0000 \u0000 \u0000Keywords: \u0000 \u0000immunosuppressant; \u0000immunosuppression; \u0000transplantation","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"117 1","pages":"983-1063"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73576841","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":"Large‐Scale Synthesis","authors":"Frank Gupton","doi":"10.1002/0471266949.BMC032.PUB2","DOIUrl":"https://doi.org/10.1002/0471266949.BMC032.PUB2","url":null,"abstract":"The capability to fulfill drug substance requirements to support the various elements of pharmaceutical development is an essential component of the overall drug development process. The preparation of bulk materials for toxicology, formulation development, and clinical supplies can represent a significant challenge, depending on such factors as the molecular complexity of the drug candidate, the quantities of materials required, and the state of development of the synthetic process. As a drug candidate proceeds through the various stages of drug development and into commercial launch, the challenge of process development is to ensure the uninterrupted supply of drug substance without compromising the ability to ultimately supply a commercially viable chemical process. This chapter provides a general overview of the issues and requirements associated with the development and scale-up of chemical processes for bulk active drug substances. An account of the nevirapine process development efforts at Boehringer Ingelheim is also provided as an example of the evolution of a chemical process from the initial efforts in medicinal chemistry to commercial-scale operations. \u0000 \u0000 \u0000Keywords: \u0000 \u0000active pharmaceutical ingredients; \u0000drug development process; \u0000in-process controls; \u0000process chemist; \u0000process development","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"1 1","pages":"1-24"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78163415","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":"Cost‐Effectiveness Analyses Throughout the Drug Development Life Cycle","authors":"R. Arnold","doi":"10.1002/0471266949.BMC161","DOIUrl":"https://doi.org/10.1002/0471266949.BMC161","url":null,"abstract":"Cost-effectiveness analysis (CEA) is a systematic, quantitative method for summarizing health benefits and health resources of various treatment options into single numbers or ratios so that policy makers can choose among them. Computer modeling of cost-effectiveness may play a significant role in informing the pharmaceutical decision-making process throughout a product's life cycle, increasing the likelihood of reimbursement and broad use. \u0000 \u0000 \u0000Keywords: \u0000 \u0000cost-effectiveness; \u0000decision analysis; \u0000economics; \u0000modeling","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82695918","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":"Atherosclerosis II: HDL Elevation","authors":"Amjad Ali, J. A. Hunt, P. Sinclair","doi":"10.1002/0471266949.BMC193","DOIUrl":"https://doi.org/10.1002/0471266949.BMC193","url":null,"abstract":"Atherosclerosis is an arterial disease associated with elevated plasma lipid levels and is a major cause of morbidity and mortality worldwide. Clinical trials have demonstrated that reduction of low-density lipoprotein cholesterol (LDL-C), as can be accomplished with HMG-CoA reductase inhibitors (statins), leads to a reduction in coronary events and mortality by about 25%. Conversely, epidemiological evidence indicates that high-density lipoprotein cholesterol (HDL-C) levels have an inverse correlation with risk of coronary artery disease. The beneficial effects of HDL have been attributed to its involvement in the movement of cholesterol from the periphery to the liver as well as to its apparent antioxidant and anti-inflammatory activities. Consequently, there is much interest in identifying therapeutic approaches to raising HDL that will be useful as a treatment for atherosclerosis and dyslipidemias. The properties and physiologic role of HDL, as well as approaches to increasing plasma HDL concentrations, will be summarized. \u0000 \u0000 \u0000Keywords: \u0000 \u0000atherosclerosis; \u0000CETP; \u0000HDL; \u0000LDL; \u0000niacin","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"13 1","pages":"331-364"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85234650","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}