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Current opinion in drug discovery & development最新文献

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GPR119 agonists: a promising new approach for the treatment of type 2 diabetes and related metabolic disorders. GPR119激动剂:治疗2型糖尿病及相关代谢紊乱的新方法
Current opinion in drug discovery & development Pub Date : 2009-07-01
Unmesh Shah
{"title":"GPR119 agonists: a promising new approach for the treatment of type 2 diabetes and related metabolic disorders.","authors":"Unmesh Shah","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Type 2 diabetes (T2D) and associated obesity have reached epidemic proportions, and there is an increasing need for orally effective agents that regulate glucose homeostasis with a concurrent reduction in body weight. GPR119, a class-A (rhodopsin-like) G protein-coupled receptor, expressed primarily in the human pancreas and gastrointestinal tract, has attracted considerable interest as a T2D drug target in the last three to five years. The activation of GPR119 increases the intracellular accumulation of cAMP, leading to enhanced glucose-dependent insulin secretion and increased levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic peptide). In rodent models, orally available GPR119-specific agonists have been shown to attenuate blood glucose levels with a simultaneous body weight loss. This review summarizes the research leading to the identification of GPR119 as a potential drug target for T2D and related metabolic disorders. In addition, an overview of the recent progress made in the discovery of orally active GPR119 agonists is provided.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28348508","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 progress in the discovery and development of negative allosteric modulators of mGluR5. mGluR5负变构调节剂的研究进展。
Current opinion in drug discovery & development Pub Date : 2009-07-01
Craig W Lindsley, Kyle A Emmitte
{"title":"Recent progress in the discovery and development of negative allosteric modulators of mGluR5.","authors":"Craig W Lindsley,&nbsp;Kyle A Emmitte","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGluR5) have attracted significant interest in the pharmaceutical industry as potential therapies for a variety of diseases of the CNS. Well-characterized small-molecule mGluR5 NAMs have demonstrated efficacy in several preclinical models of disease, and examples of the clinical efficacy of such NAMs have been reported in recent years. Advances, both in the discovery and development of new small molecules and in the clinical evaluation of known compounds, have been significant in the past 2 years. Recent progress in preclinical drug discovery efforts has used multiple strategies for the discovery of new chemical scaffolds, including the structural modification of known compounds, the rational design of new chemical scaffolds based on known compounds, and the development of screening approaches for new, structurally distinct scaffolds. Progress in the clinical setting with mGluR5 NAMs has also resulted in important recent advances, including the completion of proof-of-concept studies.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28272297","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
Personalized medicine: a paradigm for a sustainable pharmaceutical industry? 个性化医疗:可持续制药行业的典范?
Current opinion in drug discovery & development Pub Date : 2009-07-01
Samuel Chackalamannil, Manoj C Desai
{"title":"Personalized medicine: a paradigm for a sustainable pharmaceutical industry?","authors":"Samuel Chackalamannil,&nbsp;Manoj C Desai","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Personalized medicine is a custom-tailored approach to patient treatment based on individual genetic traits. In personalized medicine, a patient group is characterized by a clinical biomarker that has been correlated to a differential response to drug treatment. During the past decade, several developments in the understanding of the structure and function of the human genome have occurred that bring personalized medicine closer to becoming a reality. The promise of personalized medicine lies in a clinical biomarker-driven patient stratification, and focused smaller-sized clinical trials that result in a shorter development time and reduced overall development cost. Personalized medicine has the potential to offer a new business model for the pharmaceutical industry by providing a more efficient drug discovery process with reduced cost.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28272296","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
Direct Factor Xa and direct thrombin inhibitors: a clinical trial update. 直接Xa因子和直接凝血酶抑制剂:临床试验更新。
Current opinion in drug discovery & development Pub Date : 2009-07-01
Alexander G G Turpie
{"title":"Direct Factor Xa and direct thrombin inhibitors: a clinical trial update.","authors":"Alexander G G Turpie","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Anticoagulant use is recommended for the prevention and treatment of several thromboembolic disorders including venous thromboembolism. However, anticoagulants are often underprescribed because of the disadvantages associated with conventional agents, including the requirement for routine clinical monitoring and parenteral administration. Recent research has focused on the development of agents that target specific factors in the coagulation cascade, primarily Factor (F)Xa and thrombin. There are several new, targeted oral anticoagulants in development that could potentially provide more effective and more convenient anticoagulation than conventional agents. This review provides an update on clinical trials of the direct FXa and thrombin inhibitors.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28348506","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
Small molecules targeting sodium and calcium channels for neuropathic pain. 靶向钠钙通道的小分子治疗神经性疼痛。
Current opinion in drug discovery & development Pub Date : 2009-07-01
Brian Bear, Juliana Asgian, Andreas Termin, Nicole Zimmermann
{"title":"Small molecules targeting sodium and calcium channels for neuropathic pain.","authors":"Brian Bear,&nbsp;Juliana Asgian,&nbsp;Andreas Termin,&nbsp;Nicole Zimmermann","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Neuropathic pain is a chronic disease, which impacts millions of individuals worldwide. The condition is currently treated with several drugs that provide pain relief that is inconsistent and complicated by CNS or cardiovascular (CV) side effects. Voltage-gated sodium channels (VGSCs) and voltage-gated calcium channels (VGCCs) are of particular interest as targets for neuropathic pain because they control electrical signals in both the central and peripheral nervous system. Recent research has demonstrated that the expression of voltage-gated ion channels changes significantly under conditions of neuropathic pain in rodents and humans. Selective modulation of the channels involved in the pathology of the disease, while sparing the channels that are essential for normal nociception, offers promising opportunities for therapeutic intervention. This review summarizes recent developments of small molecules that target VGSCs and VGCCs.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28348510","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
Glycine transport inhibitors for the treatment of schizophrenia: symptom and disease modification. 甘氨酸转运抑制剂治疗精神分裂症:症状和疾病改变。
Current opinion in drug discovery & development Pub Date : 2009-07-01
Daniel C Javitt
{"title":"Glycine transport inhibitors for the treatment of schizophrenia: symptom and disease modification.","authors":"Daniel C Javitt","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Schizophrenia is a severe neuropsychiatric disorder for which there is no adequate current treatment. Recent theories about the molecular basis of schizophrenia focus on disturbances of glutamatergic neurotransmission, particularly at NMDA-type glutamate receptors (NMDARs). NMDARs are regulated in vivo by the amino acids glycine and D-serine. Glycine levels, in turn, are regulated by glycine transporter type 1 (GlyT1), which serves to maintain low subsaturating glycine levels in the vicinity of the NMDAR. Therefore, one proposed approach to the treatment of schizophrenia is via the inhibition of GlyT1-mediated transport. During the past decade, several well-tolerated, high-affinity glycine transport inhibitors (GTIs) have been developed that demonstrate the ability to potentiate NMDAR-mediated neurotransmission in animal models relevant to schizophrenia. In addition, clinical trials have been conducted with sarcosine (N-methylglycine), a naturally occurring GTI. Issues related to clinical proof-of-concept studies with high-affinity GTIs in schizophrenia are discussed in this review.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28272299","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
Prospects for the development of fusion inhibitors to treat human respiratory syncytial virus infection. 融合抑制剂治疗呼吸道合胞病毒感染的发展前景。
Current opinion in drug discovery & development Pub Date : 2009-07-01
Jean-François Bonfanti, Dirk Roymans
{"title":"Prospects for the development of fusion inhibitors to treat human respiratory syncytial virus infection.","authors":"Jean-François Bonfanti,&nbsp;Dirk Roymans","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Human respiratory syncytial virus (hRSV) is a significant cause of respiratory illness in at-risk pediatric patients, immunocompromised adults and the elderly. No vaccine is currently available for the virus and treatment options are limited to the prophylactic treatment of at-risk infants with the mAb palivizumab (Synagis) and to therapeutic intervention with the nucleoside analog ribavirin (Rebetol). The clinical use of these agents is limited and a need exists for more effective treatment for the at-risk population. The merging of viral and cellular membranes is a crucial event in the hRSV life cycle that enables the virus to enter a host cell. The multistep fusion process is facilitated by the substantial refolding of a trimeric class I fusion protein (F protein), which is the main target of fusion inhibitors. Several small-molecule fusion inhibitors have been discovered, of which some have progressed significantly in the drug development process. BTA-9881 (Biota Holdings Ltd/MedImmune) and TMC-353121 (Johnson & Johnson) are the most advanced of this drug class. In addition, progress has been made in the development of next-generation antibodies such as motavizumab (Numax; MedImmune). This review will discuss the status and latest developments of compounds and antibodies that inhibit hRSV fusion.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28272300","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
Physiologically based pharmacokinetic (PBPK) modeling and simulation: applications in lead optimization. 基于生理的药代动力学(PBPK)建模和模拟:在导联优化中的应用。
Current opinion in drug discovery & development Pub Date : 2009-07-01
Sheila Annie Peters, Anna-Lena Ungell, Hugues Dolgos
{"title":"Physiologically based pharmacokinetic (PBPK) modeling and simulation: applications in lead optimization.","authors":"Sheila Annie Peters,&nbsp;Anna-Lena Ungell,&nbsp;Hugues Dolgos","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Physiologically based pharmacokinetics (PBPK) models are increasingly being used in the lead optimization (LO) process. Although there are currently few literature reports of the application of PBPK, the scope of PBPK modeling is expanding and there is a steady increase in the number of publications in this field. Recent publications covering four important areas of the application of PBPK modeling in LO have been reviewed.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28348507","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
Current developments in and importance of high-performance computing in drug discovery. 高性能计算在药物发现中的重要性。
Current opinion in drug discovery & development Pub Date : 2009-05-01
Jed W Pitera
{"title":"Current developments in and importance of high-performance computing in drug discovery.","authors":"Jed W Pitera","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>A number of current trends that are being adopted to reshape the field of high-performance computing exist, including multi-core systems, accelerators, and software frameworks for large-scale intrinsically parallel applications. These trends intersect with recent developments in computational chemistry to provide new capabilities for computer-aided drug discovery. Although this review focuses primarily on the application domains of molecular modeling and biomolecular simulation, these computing changes are relevant for other computationally intensive tasks, such as instrument data processing and chemoinformatics.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28134082","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
New in protein structure and function annotation: hotspots, single nucleotide polymorphisms and the 'Deep Web'. 蛋白质结构和功能注释新进展:热点、单核苷酸多态性和“深网”。
Current opinion in drug discovery & development Pub Date : 2009-05-01
Yana Bromberg, Guy Yachdav, Yanay Ofran, Reinhard Schneider, Burkhard Rost
{"title":"New in protein structure and function annotation: hotspots, single nucleotide polymorphisms and the 'Deep Web'.","authors":"Yana Bromberg,&nbsp;Guy Yachdav,&nbsp;Yanay Ofran,&nbsp;Reinhard Schneider,&nbsp;Burkhard Rost","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The rapidly increasing quantity of protein sequence data continues to widen the gap between available sequences and annotations. Comparative modeling suggests some aspects of the 3D structures of approximately half of all known proteins; homology- and network-based inferences annotate some aspect of function for a similar fraction of the proteome. For most known protein sequences, however, there is detailed knowledge about neither their function nor their structure. Comprehensive efforts towards the expert curation of sequence annotations have failed to meet the demand of the rapidly increasing number of available sequences. Only the automated prediction of protein function in the absence of homology can close the gap between available sequences and annotations in the foreseeable future. This review focuses on two novel methods for automated annotation, and briefly presents an outlook on how modern web software may revolutionize the field of protein sequence annotation. First, predictions of protein binding sites and functional hotspots, and the evolution of these into the most successful type of prediction of protein function from sequence will be discussed. Second, a new tool, comprehensive in silico mutagenesis, which contributes important novel predictions of function and at the same time prepares for the onset of the next sequencing revolution, will be described. While these two new sub-fields of protein prediction represent the breakthroughs that have been achieved methodologically, it will then be argued that a different development might further change the way biomedical researchers benefit from annotations: modern web software can connect the worldwide web in any browser with the 'Deep Web' (ie, proprietary data resources). The availability of this direct connection, and the resulting access to a wealth of data, may impact drug discovery and development more than any existing method that contributes to protein annotation.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28134084","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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