Burger's Medicinal Chemistry and Drug Discovery最新文献

{"title":"Atherosclerosis: Cholesterol Management","authors":"S. Edmondson, D. Burnett, Harry R. Davis","doi":"10.1002/0471266949.bmc185.pub2","DOIUrl":"https://doi.org/10.1002/0471266949.bmc185.pub2","url":null,"abstract":"Cardiovascular disease (CVD) in all its forms remains the single most common cause of death in the United States and the industrialized world [1, 2]. In the United States, CVD was responsible for over 840 000 deaths in 2016 and the associated direct and indirect costs to the US economy were estimated to be $351.1 billion in 2014–2015 [3]. The principal components of CVD included in these numbers are coronary heart disease (CHD), stroke, heart failure, and congenital heart disorders. Atherosclerosis, the chronic inflammatory arterial wall disease associated with the deposition of cholesterol into arterial plaques and hardening of the arteries, is a major contributor to CHD and is the principal cause of heart attacks and stroke. Although there are multiple risk factors for CHD including age, family history, obesity, sedentary lifestyle, smoking, diabetes, and high blood pressure, the risk factor most closely associated with a higher incidence of CHD is serum cholesterol levels. Cholesterol is carried in vivo in lipoprotein particles of varying density and with differing surface proteins. Low-density lipoproteins (LDLs) have been shown to cause atherosclerosis, and they have a cumulative effect [4]. High-density lipoproteins (HDLs) have also been hypothesized to be cardioprotective. This article focuses mainly on therapeutic agents that lower low-density lipoprotein cholesterol (LDL-C) levels as these agents have progressed to market for the treatment and/or prevention of atherosclerosis. Lipoproteins are lipid–protein complexes consisting of surface apoproteins, a phospholipid monolayer, and free cholesterol, with cores containing neutral lipids including triglycerides (TGs) and cholesteryl esters (CEs). As shown in Figure 1, LDL are derived from very-low-density lipoproteins (VLDLs) synthesized by the liver [5]. Hepatocytes package TGs and cholesterol along with apoprotein B (isoform B100) and phospholipids to form the TG-rich lipoprotein VLDL for secretion into plasma. VLDL TGs are hydrolyzed by lipoprotein lipase (LPL), releasing free fatty acids, which reduces the size of VLDL to intermediate-density lipoproteins (IDLs). IDL TGs are hydrolyzed by hepatic lipase, forming LDL that contains one molecule of apoB and primarily esterified cholesterol in its core. VLDL, IDL, and LDL obtain CEs through the exchange of TGs and CEs from HDLs by the activity of cholesteryl ester transfer protein (CETP). LDL transports cholesterol to peripheral tissues where it is taken up by the low-density lipoprotein receptor (LDL-R) [6]. LDL is cleared from the circulation primarily by hepatic LDL-Rs. LDL-Rs bind apoB and apoE enriched lipoproteins like LDL, internalize LDL through clathrin-coated pits, release the LDL into acidified endosomes, and the LDL-R recycles to the cell surface to bind additional LDL particles. Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) binds to the LDL-R and directs it to be degraded, interrupting the recycling LDL-R pathway (","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90747099","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":"Hematopoietic Agents","authors":"Jonathan Hoggatt, Shruti Datari, L. Pelus","doi":"10.1002/0471266949.bmc045.pub3","DOIUrl":"https://doi.org/10.1002/0471266949.bmc045.pub3","url":null,"abstract":"","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"179 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80067427","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":"Chemical Perspective on Neurotransmission and Drug Discovery for the Central Nervous System","authors":"R. Mailman, K. Vrana","doi":"10.1002/0471266949.BMC245","DOIUrl":"https://doi.org/10.1002/0471266949.BMC245","url":null,"abstract":"In this chapter, we review the evolution of approaches that have influenced the drug discovery and medicinal chemistry of agents active in the central nervous system (CNS). While Ehrlich's century-old concept of the magic bullet governed the theory of discovery, the reality was driven for decades by what might be termed exploited serendipity. This changed markedly when, first, radioreceptor assays became widely available, and soon thereafter, when molecular biology gave the field first cloned receptors, and later the whole-genome. Although of immense scientific use, these advances did not yield a pipeline flooded with novel drugs. They have, however, provided the tools needed for truly innovative drug discovery. Several newer concepts have now been shown to offer future directions for drug discovery. First, it is clear that drugs that target several receptors (magic shotguns) can sometimes provide CNS clinical profiles not achievable by magic bullets. Second, the use of allosteric ligands that target sites of receptors or proteins distant from the binding site of their endogenous ligands or substrates has opened new horizons for modulation, activation, or blockade of difficult targets. Finally, the definitions of agonist or antagonist have become complicated by the concept of functional selectivity, the phenomenon where a single ligand acting at the same molecular target can differentially affect the signaling pathways mediated by the receptor. These newer ideas make the importance of collaboration between biologist and chemist even more crucial, and while complicating our concepts of drug action, provide a future richness of discovery opportunity. \u0000 \u0000 \u0000Keywords: \u0000 \u0000allosteric ligands; \u0000cotransmission; \u0000functional selectivity; \u0000multitargeting drugs; \u0000receptor function; \u0000screening approaches","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"3 1","pages":"1-14"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74522208","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":"Histone Deacetylase Inhibitors: A Brief Overview Of Their Role And Medicinal Chemistry","authors":"P. Angibaud, K. V. Emelen, J. Arts","doi":"10.1002/0471266949.BMC213","DOIUrl":"https://doi.org/10.1002/0471266949.BMC213","url":null,"abstract":"Histone deacetylases (HDACs) comprise a family of proteins that impact critical cellular processes through regulation of chromatin remodeling and gene transcription. HDACs have emerged as attractive targets for the development of new anticancer agents and a number of structurally diverse inhibitors of HDAC from natural or synthetic origin have been described in the literature. This chapter focuses on those having reached clinical phases. For each, synthesis pathway, in vitro properties and short clinical profiles are presented. Recent developments in medicinal chemistry of HDAC inhibition are also reported. \u0000 \u0000 \u0000Keywords: \u0000 \u0000anticancer-agents; \u0000chromatin; \u0000HDAC; \u0000JNJ-26481585; \u0000histone deacetylase; \u0000hydroxamic acid; \u0000R306465","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"53 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75337965","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":"Agents Acting on Prostanoid and Thromboxane Receptors","authors":"A. Hall, Simon Peace, M. Swarbrick","doi":"10.1002/0471266949.BMC064.PUB2","DOIUrl":"https://doi.org/10.1002/0471266949.BMC064.PUB2","url":null,"abstract":"This chapter covers recent developments in the prostaglandin and thromboxane research area, with particular focus on the medicinal chemistry aspects. Each of the receptors is discussed in turn with progress and medicinal chemistry strategies discussed for both agonists and antagonists. Clinical development compounds are highlighted.Keywords:prostaglandins;thromboxane;antagonist;agonist;eicosanoid","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"51 1","pages":"791-944"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74258217","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 Development, Validation, and Exploitation of QSAR Models","authors":"A. Tropsha","doi":"10.1002/0471266949.BMC002.PUB2","DOIUrl":"https://doi.org/10.1002/0471266949.BMC002.PUB2","url":null,"abstract":"Counting more than 45 years of intensive development and applications, QSAR modeling remains one of the major computational approaches for drug discovery and environmental chemical risk assessment. Recent developments in the field reflect the burgeoning growth of bioactivity and chemical databases. This growth provides a never-ending impetus for the development of a growing body of QSAR models and their application for virtual screening to prioritize chemicals for experimental investigations. This chapter reviews recent and emerging trends in the QSAR modeling field with the emphasis on new approaches to chemical and biological data curation, model validation, virtual screening, and potential application of QSAR models by federal agencies for regulatory decision making. \u0000 \u0000 \u0000Keywords: \u0000 \u0000databases; \u0000data curation; \u0000modeling workflow; \u0000model validation; \u0000virtual screening","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81290625","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":"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}