1,721,004 research outputs found
SYMMETRICAL 2-AMINOPHENYL-BENZAZOLYL-5-ACETATE COMPOUNDS AND THEIR USE AS ANTI-HEPARANASE
No full textThe present invention relates to symmetrical 2-aminophenyl-benzazolyl-5-acetate compoundsof formula (I). Such compounds are endowed with an anti-heparanase activity. The present invention also relates to the use of such compounds as a medicament, in particular for the treatment of diseases and disorders associated with a heparanase activity, and to pharmaceutical compositions comprising the same
Discovery of quinolinonyl derivatives as anti-HIV-1 inhibitors endowed with an innovative mechanism of action.
No full textHIV integrase (IN) is a pivotal antiretroviral drug target. In this regard, IN strand transfer inhibitors (INSTIs), binding to the IN active site, have proven to be highly effective, becoming a potent first-line therapy to treat infected patients. However, despite their effectiveness as therapeutic options and the high barriers with the second-generation FDA-approved INSTIs, drug therapy selects for drug resistance and mutations responsible for multiple INSTIs resistance, underscoring the need for the development of more effective antiretroviral compounds. The development of small molecule protein-protein interaction inhibitors is a new attractive strategy for discovering anti-HIV agents. In this field of research, allosteric IN inhibitors (ALLINIs), are a promising new class of antiretroviral agents. These inhibitors act differently in respect to INSTIs, in fact, they alter the functional IN multimerization. Recently, it was unraveled that aberrant IN multimerization underlies the inhibition of IN-vRNA interactions by ALLINIs. In doing so, ALLINIs indirectly disrupt the IN-vRNA binding, leading to the formation of defective viral particles with greatly reduced infective potential with mis-localization of the vRNA outside the viral capsid. While the indirect disruption of IN-vRNA binding (caused by the impairment of functional IN multimerization) has been described with the treatment of virus-producing cells with ALLINIs, the direct disruption of this binding (without affecting IN multimerization properties) by small molecules has not been reported so far. We describe a series of compounds identified as inhibitors of the IN-vRNA binding via a direct mechanism. In particular, we deepened the mechanism of action of some compounds previously described by us as INSTIs. Indeed, we speculated that these quinolinonyl derivatives, being endowed with two DKA chains, could also act as protein-nucleic acid interaction inhibitors. To verify our hypothesis, we decided to test a set of derivatives and their analogues endowed with a variable “base-like” functional group. We assessed the capability of our derivatives of inhibiting at low micromolar concentrations both IN 3’-processing and strand transfer reactions in a LEDGF/p75 independent assay. In addition, we performed in vitro binding assays, and we found that our quinolinonyl derivatives are able to disrupt the IN-vRNA interaction, that is vital for a correct generation of a functional infective virion. The data coming from the biological assays will be shown and discussed
From Iloperidone to new Sigma1 agonists: a structure-based approach for Huntington's disease treatment.
No full textHuntington's disease (HD) is an autosomal dominant disorder caused by a mutation in the HTT gene, which progressively leads neurons in parts of the brain to break down and die. Unfortunately, to date there are no effective treatments that can stop or prevent the onset of this devastating disease. However, recent and growing numbers of studies are showing how the sigma-1 receptor (σ1R) may be implicated in the control of several neurodegenerative disorders, including HD. The σ1R is a small and poorly understood membrane receptor expressed in the central nervous system, whose 3D structure has been recently determined by X-ray crystallography and responding to different synthetic ligands such as (+)-pentazocine (agonist) and haloperidol (antagonist). Substantial evidence suggests that knockdown or antagonism of the σ1R has analgesic effects, while agonists have been shown to have neuroprotective activity in neurodegenerative diseases. Nevertheless, the structural basis for agonism or antagonism on σ1R is largely unknown. In general, the overall conformation of the receptor bound to the agonist crystallizes similarly to that bound to the antagonist, except for a shift of about 1.8Å in the α4 helix. Probably, this shift is responsible for the tendency of agonists to decrease the oligomeric state of the protein. Through structure-based computational methods, we aim to design new small molecules as σ1R modulators. Indeed, very recently, a high binding affinity for the σ1R of the antipsychotic Iloperidone has been demonstrated. From our early studies, the pharmacophoric groups have emerged. In detail, the most stable interactions are established by the nitrogen atom of the piperidine ring of Iloperidone, which is positively charged at physiological pH. This charge allows the molecule to interact with the Phe107 of protein and the negatively charged Glu172 residue. Starting to these data, the chemical structure of this antipsychotic drug will be modified applying a scaffold hopping approach, in order to obtain a pronounced and selective agonist of the σ1R
Acetylcholinesterase inhibitors for the treatment of Alzheimer’s disease – a patent review (2016–present)
No full textIntroduction - AD, the most common form of dementia, has a multifactorial etiology, and the current therapy (AChEIs and memantine) is unable to interrupt its progress and fatal outcome. This is reflected in the research programs that are oriented toward the development of new therapeutics able to operate on multiple targets involved in the disease progression.Areas covered - The patents from 2016 to present regarding the use of AChEIs in AD, concerns the development of new AChEIs, multitarget or multifunctional ligands, or the associations of currently used AChEIs with other compounds acting on different targets involved in the AD.Expert opinion - The development of new multitarget AChEIs promises to identify compounds with great therapeutic potential but requires more time and effort in order to obtain drugs with the optimal pharmacodynamic profile. Otherwise, the research on new combinations of existing drugs, with known pharmacodynamic and ADME profile, could shorten the time and reduce the costs to develop a new therapeutic treatment for AD. From the analyzed data, it seems more likely that a response to the urgent need to develop effective treatments for AD therapy could come more quickly from studies on drug combinations than from the development of new AChEIs
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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