Recent patents on CNS drug discovery最新文献

{"title":"Recent developments in tau-based therapeutics for neurodegenerative diseases.","authors":"Miguel Medina","doi":"10.2174/157488911794079091","DOIUrl":"https://doi.org/10.2174/157488911794079091","url":null,"abstract":"<p><p>Neurodegenerative diseases constitute a major public health issue due to an increasingly aged population as a consequence of generally improved medical care and demographic changes. Current drug treatment of Alzheimer's disease (AD), the most prevalent dementia, with cholinesterase inhibitors or NMDA antagonists has demonstrated very modest, symptomatic efficacy, leaving an unmet medical need for new, more effective therapies. Drug development efforts for AD in the last two decades have primarily focused on targets defined by the amyloid cascade hypothesis, so far with disappointing results. In contrast, tau-based strategies have received little attention until recently despite that the presence of extensive tau pathology is central to the disease. The discovery of mutations within the tau gene that cause fronto-temporal dementia demonstrated that tau dysfunction, in the absence of amyloid pathology, was sufficient to cause neuronal loss and clinical dementia. This review focuses on emerging therapeutic strategies aimed at treating the underlying causes of the tau pathology in tauopathies and AD, including some targets with significant potential in the field and which might be on the verge of providing new treatment paradigms within the coming years. Among those strategies, immunotherapy approaches will be mostly discussed. An update on 2010 patents regarding different aspects of tau-based therapeutic strategies is also provided.</p>","PeriodicalId":87737,"journal":{"name":"Recent patents on CNS drug discovery","volume":"6 1","pages":"20-30"},"PeriodicalIF":0.0,"publicationDate":"2011-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/157488911794079091","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29501600","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":"Do we need a new procedure for the assessment of adverse events in anti-migraine clinical trials?","authors":"Martina Amanzio","doi":"10.2174/157488911794079109","DOIUrl":"10.2174/157488911794079109","url":null,"abstract":"<p><p>The large number of randomized controlled clinical trials on migraine have drawn the attention of some authors to the need to improve the design of such trials. In particular, adequate methodology is a critical issue in their planning and execution, as different methodological approaches can translate into different results. The side-effects observed in both the active medication arm and the placebo arm--considering anti-migraine randomized clinical trials--are often influenced by non specific factors. This issue can be quantified by using a systematic review approach to study the rates of adverse events reported in the placebo arms of clinical trials. Such a study requires increased standardization of the methods used to collect adverse data in clinical trials. This focused review article provides a critical re-analysis of the results obtained, by our group, in a recent systematic review of adverse events reported in the placebo groups of clinical trials for three classes of anti-migraine drugs: NSAIDs, triptans and anticonvulsants [Amanzio et al., 2009]. We consider the need for caution in interpreting side-effect profiles of the different placebo groups. In particular, since the side-effects observed in both the active medication and placebo arms of randomized clinical trials are often influenced by patients' and investigators' expectations, the nocebo phenomenon may help to understand the occurrence of (adverse) non-specific side effects observed in these groups. We also discuss the importance of evaluating the role of contributing factors in the results obtained, such as the need for the examiner to be blind to the expected side-effects of the drug being evaluated and a better rationalization of informed consent in order to avoid the occurrence of negative expectations in patients, aimed at preventing negative expectation effects among both investigators and patients. Currently, there is one patented design for investigating reductions in the placebo effect in controlled clinical trials. This paper discusses how these ideas may be helpful in the assessment of adverse events in active and placebo groups.</p>","PeriodicalId":87737,"journal":{"name":"Recent patents on CNS drug discovery","volume":"6 1","pages":"41-7"},"PeriodicalIF":0.0,"publicationDate":"2011-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29501602","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":"Towards drug discovery for brain tumours: interaction of kinins and tumours at the blood brain barrier interface.","authors":"Elizabeth Harford-Wright,&nbsp;Kate M Lewis,&nbsp;Robert Vink","doi":"10.2174/157488911794079118","DOIUrl":"https://doi.org/10.2174/157488911794079118","url":null,"abstract":"<p><p>Cancers of the brain are intrinsically more complicated to treat than systemic malignancies due to the unique anatomical features of the brain. The blood-brain barrier prevents chemotherapeutic agents from reaching brain neoplasms, and angiogenesis occurs as the metabolic needs of the tumour increase, thus further complicating treatment. The newly formed blood vessels form the blood-tumour barrier and are distinct from the blood-brain barrier in that they are more permeable. Being more permeable, these abnormal blood vessels lead to the formation of peri-tumoural edema, which is the cause of much morbidity and mortality associated with central nervous system neoplasms. While the cause of the increased permeability is unclear, kinins have been implicated in regulating the permeability of normal vasculature. Kinins are also known to exert many inflammatory actions affecting both normal and angiogenic blood vessels, as well as tumour cells. The vasodilatory and vascular permeabilizing effects of kinins, and particularly bradykinin and substance P, have been investigated with regard to delivery of chemotherapeutic agents to neoplastic brain tissue through both vascular barriers. In contrast, kinin receptor antagonists have been found to exert effects on tumour cells that result in decreased angiogenesis, tumour cell motility and growth. Thus, many recent patents describe kinin activity on brain vasculature, which may play an integral role in the development of treatments for malignancies in the central nervous system through amelioration of angiogenesis. In conjunction, patents that discuss the ability of kinins to decrease tumour cell migration and proliferation demonstrate that kinins may offer novel approaches to brain tumour therapy in the future.</p>","PeriodicalId":87737,"journal":{"name":"Recent patents on CNS drug discovery","volume":"6 1","pages":"31-40"},"PeriodicalIF":0.0,"publicationDate":"2011-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/157488911794079118","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29465744","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":"PTI-609: a novel analgesic that binds filamin A to control opioid signaling.","authors":"Lindsay H Burns,&nbsp;Hoau-Yan Wang","doi":"10.2174/157488910793362386","DOIUrl":"https://doi.org/10.2174/157488910793362386","url":null,"abstract":"<p><p>Binding a critical pentapeptide region on the scaffolding protein filamin A regulates signaling of mu opioid receptors (MORs) so that their activation should not result in the opioid tolerance, dependence and addiction associated with current opioid painkillers. Additionally, we show that compounds that bind this site on filamin A reduce release of inflammatory cytokines. PTI-609 is a new chemical entity that binds filamin A with picomolar affinity and also activates opioid receptors via a novel binding domain. PTI-609 and analogs have similar analgesic efficacy to morphine by oral administration in mice, provide some anti-inflammatory activity in the rat collagen-induced arthritis model, and show no conditioned place preference at analgesic doses, suggesting no potential for abuse and addiction. PTI-609 was designed after discovering filamin A as the high-affinity target of naltrexone or naloxone. Combined with opiates, ultra-low-dose naloxone or naltrexone can enhance and prolong the analgesia of the opiate alone and prevent or attenuate opioid tolerance, dependence and addictive properties. We will review here the mechanism of action of ultra-low-dose naltrexone and naloxone, the discovery of filamin A as their high-affinity target, and the rationale as to why the current, dualfunction new chemical entity should not only be easier to develop but also more consistently efficacious than opioids combined with ultra-low-dose naltrexone. This new class of compounds, as well as the concept, screening assay and pharmacophore model, are covered in a family of recent patent applications.</p>","PeriodicalId":87737,"journal":{"name":"Recent patents on CNS drug discovery","volume":"5 3","pages":"210-20"},"PeriodicalIF":0.0,"publicationDate":"2010-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/157488910793362386","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29204335","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":"Pharmacological therapy of Parkinson's disease: current options and new avenues.","authors":"Nicola Simola,&nbsp;Annalisa Pinna,&nbsp;Sandro Fenu","doi":"10.2174/157488910793362421","DOIUrl":"https://doi.org/10.2174/157488910793362421","url":null,"abstract":"<p><p>Parkinson's disease is a neurodegenerative pathology which affects the dopaminergic neurons in the mesencephalon, leading to a progressive and relentless motor disability and to non-motor symptoms of different severity. The aim of this review is to summarize the features of drugs currently used in the pharmacotherapy of Parkinson's disease, with a look at their beneficial effects and limitations. Drugs acting on dopamine transmission, as L-DOPA, direct dopaminergic agonists, inhibitors for either the MAO or COMT enzymes and drugs acting on neurotransmitters other than dopamine (e.g. acetylcholine, glutamate) will be covered. Investigational drugs currently under examination for their therapeutic potential in Parkinson's disease and recent patents which may be relevant to the field will be also discussed.</p>","PeriodicalId":87737,"journal":{"name":"Recent patents on CNS drug discovery","volume":"5 3","pages":"221-38"},"PeriodicalIF":0.0,"publicationDate":"2010-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/157488910793362421","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29204339","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":"Copper status abnormalities and how to measure them in neurodegenerative disorders.","authors":"Mariacristina Siotto,&nbsp;Serena Bucossi,&nbsp;Rosanna Squitti","doi":"10.2174/157488910793362395","DOIUrl":"https://doi.org/10.2174/157488910793362395","url":null,"abstract":"<p><p>Copper is essential for life. It plays a pivotal role in the central nervous system, in which a low concentration of copper results in incomplete development, whereas an excess of copper is injurious. Redox reactions are at the basis of copper toxicity: in fact, it catalyses the production of reactive oxygen species in Fenton or Haber-Weiss reactions. Abnormalities of copper homeostasis in neurodegenerative disorders were discovered decades ago. The steady increase in reports from the literature demonstrating copper involvement in neurodegenerative disorders coincides with the improvement, reliability and low cost devices which measure copper markers in biological samples. These devices also demonstrate increasing relevance in diagnosis and in therapy monitoring as well. Methods and new perspectives for the analysis of copper markers status are discussed herein, weighing pros and cons of application to a specific neurological disorder. In particular, it have been introduced three patents regarding a new apparatus for measuring levels of metal in biological samples, employing a current measuring device. A mention of recent patents concerning new derivatives of curcumin has been done considering its metal chelating and multi-functional properties that make these compounds interesting candidates for treatment of some neurodegenerative disorders.</p>","PeriodicalId":87737,"journal":{"name":"Recent patents on CNS drug discovery","volume":"5 3","pages":"182-94"},"PeriodicalIF":0.0,"publicationDate":"2010-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/157488910793362395","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29204336","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":"Current options in the treatment of mitochondrial diseases.","authors":"Mauro Scarpelli,&nbsp;Maria Sofia Cotelli,&nbsp;Michelangelo Mancuso,&nbsp;Giuliano Tomelleri,&nbsp;Paola Tonin,&nbsp;Carla Baronchelli,&nbsp;Valentina Vielmi,&nbsp;Valeria Gregorelli,&nbsp;Alice Todeschini,&nbsp;Alessandro Padovani,&nbsp;Massimiliano Filosto","doi":"10.2174/157488910793362412","DOIUrl":"https://doi.org/10.2174/157488910793362412","url":null,"abstract":"<p><p>Mitochondrial diseases (MD) are disorders caused by an impairment of the mitochondrial respiratory chain function. They are usually progressive, isolated or multi-system diseases and have variable times of onset. Because mitochondria have their own DNA (mtDNA), MD can be caused by mutations in both mtDNA and nuclear DNA (nDNA). The complexity of genetic control of mitochondrial function is in part responsible for the intra- and inter-familiar clinical heterogeneity of this class of diseases. Despite the remarkable progress in understanding of the molecular bases of these disorders, therapy of MD is quite inadequate. Present options of treatment mainly include physical, pharmacological and gene therapy approaches. Aerobic exercise and physical therapy is useful to prevent or correct deconditioning and may improve exercise tolerance. Pharmacological approach is based on removing noxious metabolites, using reactive oxygen species scavengers and administrating vitamins and cofactors which is especially important in case of primary deficiencies of specific compounds such as Coenzyme Q10. Gene therapy is fascinating but it is difficult to apply because of polyplasmy and heteroplasmy. Experimental methods include gene shifting, allotopic expression, mitochondrial transfection or correcting mtDNA mutations with specific restriction endonucleases. Here, we discussed some recent patents. Progresses in each of these fields may open interesting perspectives for the future.</p>","PeriodicalId":87737,"journal":{"name":"Recent patents on CNS drug discovery","volume":"5 3","pages":"203-9"},"PeriodicalIF":0.0,"publicationDate":"2010-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/157488910793362412","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29199165","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":"On the future development of optimally-sized lipid-insoluble systemic therapies for CNS solid tumors and other neuropathologies.","authors":"Hemant Sarin","doi":"10.2174/157488910793362403","DOIUrl":"https://doi.org/10.2174/157488910793362403","url":null,"abstract":"<p><p>It remains a challenge to deliver effective concentrations of therapeutics into CNS pathologies, which is primarily due to the fact that current and investigational CNS therapeutics are suboptimally-sized to accumulate to effective concentrations in individual diseased CNS tissue cells. The blood-CNS barrier of blood capillary microvasculature within neuropathologic tissues is known to be permeable to lipid-insoluble macromolecules in a wide-spectrum of neuropathologies. In the case of CNS solid tumor tissue blood capillaries, the physiological upper limit of pore size to the transcapillary passage of spherical lipid-insoluble macromolecules is approximately 12 nanometers, and systemically administered imageable dendrimer nanoparticles within the 7 to 10 nanometer size range accumulate to therapeutic concentrations in solid tumors since this size range of particles maintain peak blood concentrations for several hours. In preliminary pre-clinical studies, it has recently been shown that one intravenous dose of small molecule chemotherapy-conjugated imageable dendrimer nanoparticles within the 7 to 10 nanometer size range, with doxorubicin bound to the particle exterior via acid-labile covalent linkages, is effective at regressing orthotopic rodent malignant gliomas. Although it is foreseeable that such drug-conjugated imageable nanoparticles within the 7 to 10 nanometer size range will be effective theranostic agents for the concurrent treatment (i.e. neutron capture therapy) and imaging (i.e. magnetic resonance) of solid tumor disease, the issue of maintaining a neutralized particle exterior following the attachment of cationic drugs will need to be addressed to eliminate cationic charge-mediated nanoparticle toxicity to blood capillary walls. In this review, the ultrastructural basis for blood capillary microvascular permeability to lipid-insoluble macromolecules is discussed, and the importance of delineating the precise physiologic upper limits of pore size in the blood capillary microvasculature of other CNS pathologies, including neurodegenerative, inflammatory and ischemic CNS diseases, is emphasized. The discussion herein will serve as guide for the future development of optimally-sized, non-toxic and non-immunogenic lipid-insoluble systemic therapies, which should be the focus of future patent applications and patents on CNS drug development.</p>","PeriodicalId":87737,"journal":{"name":"Recent patents on CNS drug discovery","volume":"5 3","pages":"239-52"},"PeriodicalIF":0.0,"publicationDate":"2010-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/157488910793362403","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29199166","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":"Transglutaminases as possible therapeutic targets in neurodegenerative diseases.","authors":"Antonio Martin,&nbsp;Giulia De Vivo,&nbsp;Mariangela Ricotta,&nbsp;Maura Iannuzzi,&nbsp;Vittorio Gentile","doi":"10.2174/157488910793362430","DOIUrl":"https://doi.org/10.2174/157488910793362430","url":null,"abstract":"<p><p>Transglutaminases are ubiquitous enzymes which catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted /crosslinked adducts) or -OH groups (to form ester linkages). In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Recently, \"tissue\" transglutaminase, a member of the transglutaminase family of enzymes, has been shown to be involved in the molecular mechanisms responsible for a very widespread human pathology, celiac disease. Transglutaminase activity has also been hypothesized to be involved in the pathogenetic mechanisms responsible for several other human diseases, including neurodegenerative diseases, often associated to celiac disease. Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, supranuclear palsy, Huntington's disease and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This review focuses on the possible therapeutic effects of transglutaminase inhibitors and their recent patents for the cure of patients with diseases characterized by aberrant transglutaminase activity and on the strategies to design such transglutaminase inhibitors.</p>","PeriodicalId":87737,"journal":{"name":"Recent patents on CNS drug discovery","volume":"5 3","pages":"195-202"},"PeriodicalIF":0.0,"publicationDate":"2010-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/157488910793362430","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29128016","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":"Neurogenic drugs and compounds.","authors":"Philippe Taupin","doi":"10.2174/157488910793362377","DOIUrl":"https://doi.org/10.2174/157488910793362377","url":null,"abstract":"<p><p>The advent of adult neurogenesis and neural stem cell (NSC) research opens new avenues and opportunities for treating neurological diseases and disorders, particularly for the discovery and development of novel drugs. Adult neurogenesis is modulated by a broad range of stimuli, physio- and pathological processes, trophic factors/cytokines and drugs, particularly drugs used for treating neurological diseases and disorders. Hence, adult neurogenesis is the target of drugs used for treating neurological diseases and disorders, such as Alzheimer's disease and depression, and the activities of neurological drugs may be mediated by adult NSCs. Although the contribution and mechanism of adult neurogenesis and newly generated neuronal cells of the adult brain in the activities of neurological drugs remain to be determined, new research is geared toward discovering and developing novel drugs that target specifically adult neurogenesis and the NSCs of the adult brain. Neurogenic drugs may reverse or compensate deficits and impairments associated with neurological diseases and disorders, particularly those associated with the hippocampus. They may have a potential for regenerative medicine and for the treatment of brain tumors. However, limitations in established models and protocols currently used in the drug discovery and development process of these drugs may hinder their potency and specificity. Here, we reviewed and discussed recent patents on neurogenic drugs and compounds, particularly nootropic agents and apigenin and related compounds.</p>","PeriodicalId":87737,"journal":{"name":"Recent patents on CNS drug discovery","volume":"5 3","pages":"253-7"},"PeriodicalIF":0.0,"publicationDate":"2010-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/157488910793362377","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29128017","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}