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Secretase Inhibitors (secretase + inhibitor)
Selected AbstractsSynthesis and Evaluation of Succinoyl-Caprolactam ,-Secretase Inhibitors.CHEMINFORM, Issue 31 2006Lorin A. Thompson Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source] A New Series of Potent Benzodiazepine ,-Secretase Inhibitors.CHEMINFORM, Issue 18 2003Ian Churcher Abstract For Abstract see ChemInform Abstract in Full Text. [source] REVIEW: ,-Secretase Inhibitors for the Treatment of Alzheimer's Disease: The Current StateCNS: NEUROSCIENCE AND THERAPEUTICS, Issue 5 2010Francesco Panza SUMMARY Aims: Drugs currently used for the treatment of Alzheimer's disease (AD) partially stabilize patients' symptoms without modifying disease progression. Brain accumulation of oligomeric species of ,-amyloid (A,) peptides, the principal components of senile plaques, is believed to play a crucial role in the development of AD. Based on this hypothesis, huge efforts are being spent to identify drugs able to interfere with proteases regulating A, formation from amyloid precursor protein (APP). This article briefly reviews the profile of ,-secretase inhibitors, compounds that inhibit ,-secretase, the pivotal enzyme that generates A,, and that have reached the clinic. Discussion: Several classes of potent ,-secretase inhibitors have been designed and synthesized. Preclinical studies have indicated that these compounds are able to lower brain A, concentrations and, in some cases, reduce A, plaque deposition in transgenic mouse models of AD. The most developmentally advanced of these compounds is semagacestat, presently in Phase III clinical trials. In animals, semagacestat reduced A, levels in the plasma, cerebrospinal fluid (CSF), and the brain. However, studies have not reported on its cognitive effects. Studies in both healthy volunteers and patients with AD have demonstrated a dose-dependent inhibition of plasma A, levels, and a recent study in healthy subjects demonstrated a robust, dose-dependent inhibition of newly generated A, in the CSF after single oral doses. Conclusions: Unfortunately, ,-secretase inhibitors may cause intestinal goblet cell hyperplasia, thymus atrophy, decrease in lymphocytes, and alterations in hair color, effects associated with the inhibition of the cleavage of Notch, a protein involved in cell development and differentiation. Nevertheless, at least other two promising ,-secretase inhibitors are being tested clinically. This class of drugs represents a major hope to slow the rate of decline of AD. [source] In silico prediction and screening of ,-secretase inhibitors by molecular descriptors and machine learning methodsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 6 2010Xue-Gang Yang Abstract ,-Secretase inhibitors have been explored for the prevention and treatment of Alzheimer's disease (AD). Methods for prediction and screening of ,-secretase inhibitors are highly desired for facilitating the design of novel therapeutic agents against AD, especially when incomplete knowledge about the mechanism and three-dimensional structure of ,-secretase. We explored two machine learning methods, support vector machine (SVM) and random forest (RF), to develop models for predicting ,-secretase inhibitors of diverse structures. Quantitative analysis of the receiver operating characteristic (ROC) curve was performed to further examine and optimize the models. Especially, the Youden index (YI) was initially introduced into the ROC curve of RF so as to obtain an optimal threshold of probability for prediction. The developed models were validated by an external testing set with the prediction accuracies of SVM and RF 96.48 and 98.83% for ,-secretase inhibitors and 98.18 and 99.27% for noninhibitors, respectively. The different feature selection methods were used to extract the physicochemical features most relevant to ,-secretase inhibition. To the best of our knowledge, the RF model developed in this work is the first model with a broad applicability domain, based on which the virtual screening of ,-secretase inhibitors against the ZINC database was performed, resulting in 368 potential hit candidates. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010 [source] Notch signaling is activated by TLR stimulation and regulates macrophage functionsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2008Tanapat Palaga Dr. Abstract Notch signaling is a well-conserved pathway involved in cell fate decisions, proliferation and apoptosis. We report on the involvement of Notch signaling in regulating gene expression in activated macrophages. Toll-like receptors (TLR) agonists such as bacterial lipopeptide, polyI:C, lipopolysaccharide and unmethylated CpG DNA all induced up-regulation of Notch1 in primary and macrophage-like cell lines. Notch1 up-regulation was dependent on the MyD88 pathway when stimulated through TLR2, but not TLR4. Activated Notch1 and expression of the Notch target genes, Hes1 and Deltex, were detected in activated macrophages, suggesting that Notch signaling was activated upon stimulation. Inhibiting processing of Notch receptor by ,-secretase using a ,-secretase inhibitor (GSI), the expression of Notch1 was down-regulated to basal levels. This treatment significantly modulated expression of TNF-,, IL-6, and IL-10. In addition, the amount of nitric oxide produced was significantly lower and the expression of MHC class II was up-regulated in GSI-treated cells. Treatment with GSI or silencing Notch1 resulted in decreased translocation of NF-,Bp50 into nucleus upon stimulation. Taken together, stimulation of macrophages through the TLR signaling cascade triggered activation of Notch signaling, which in turn regulated gene expression patterns involved in pro-inflammatory responses, through activation of NF-,B. [source] A ,-secretase inhibitor decreases amyloid-, production in the central nervous system,ANNALS OF NEUROLOGY, Issue 1 2009Randall J. Bateman MD Objective Accumulation of amyloid-, (A,) by overproduction or underclearance in the central nervous system (CNS) is hypothesized to be a necessary event in the pathogenesis of Alzheimer's disease. However, previously, there has not been a method to determine drug effects on A, production or clearance in the human CNS. The objective of this study was to determine the effects of a ,-secretase inhibitor on the production of A, in the human CNS. Methods We utilized a recently developed method of stable-isotope labeling combined with cerebrospinal fluid sampling to directly measure A, production during treatment of a ,-secretase inhibitor, LY450139. We assessed whether this drug could decrease CNS A, production in healthy men (age range, 21,50 years) at single oral doses of 100, 140, or 280mg (n = 5 per group). Results LY450139 significantly decreased the production of CNS A, in a dose-dependent fashion, with inhibition of A, generation of 47, 52, and 84% over a 12-hour period with doses of 100, 140, and 280mg, respectively. There was no difference in A, clearance. Interpretation Stable isotope labeling of CNS proteins can be utilized to assess the effects of drugs on the production and clearance rates of proteins targeted as potential disease-modifying treatments for Alzheimer's disease and other CNS disorders. Results from this approach can assist in making decisions about drug dosing and frequency in the design of larger and longer clinical trials for diseases such as Alzheimer's disease, and may accelerate effective drug validation. Ann Neurol 2009 [source] Expression and role of Notch signalling in the regeneration of rat tracheal epitheliumCELL PROLIFERATION, Issue 1 2009X.-B. Ma Objectives:, This study is to explore the role of Notch signalling during the regeneration of rat tracheal epithelium after injury induced by 5-fluorouracil (5-FU). Materials and methods:, We developed an ex vivo model of rat tracheal epithelial regeneration using 5-FU to induce injury. Expression levels of members of the Notch signalling pathway, ABCG2, CK19, and proliferating cell nuclear antigen (PCNA) were examined by reverse transcription,polymerase chain reaction, Western blot, and immunofluorescence. One group of tracheas were cultured in the medium with a ,-secretase inhibitor or Jag-1 peptide after 5-FU treatment and another group were pre-treated with the ,-secretase inhibitor or Jag-1 peptide before 5-FU treatment. The expression changes of ABCG2, CK19, and PCNA were examined by Western blot or immunofluorescence and the morphologic changes were observed by haematoxylin and eosin stain during the recovery process. Results:, Expression levels of Notch3, Jagged1, and Hey1 were increased in rat tracheal epithelial cells after treatment with 5-FU. During injury recovery, disruption of Notch signalling by treatment with the ,-secretase inhibitor reduced expression of ABCG2 and PCNA, but promoted expression of CK19, while persistent activation of Notch signalling promoted expression of ABCG2 and PCNA, but reduced expression of CK19. Under both conditions, recovery from injury was reduced. However, blocking Notch signalling prior to 5-FU treatment led to the complete blockage of recovery, while activating Notch signalling before 5-FU treatment promoted recovery. Conclusions:, During tracheal epithelial regeneration, Notch signalling maintains an undifferentiated state and promotes proliferation among a population of tracheal epithelial cells. [source] Role for notch signaling in salivary acinar cell growth and differentiationDEVELOPMENTAL DYNAMICS, Issue 3 2009Howard Dang Abstract The Notch pathway is crucial for stem/progenitor cell maintenance, growth and differentiation in a variety of tissues. The Notch signaling is essential for Drosophila salivary gland development but its role in mammalian salivary gland remains unclear. The human salivary epithelial cell line, HSG, was studied to determine the role of Notch signaling in salivary epithelial cell differentiation. HSG expressed Notch 1 to 4, and the Notch ligands Jagged 1 and 2 and Delta 1. Treatment of HSG cells with inhibitors of ,-secretase, which is required for Notch cleavage and activation, blocked vimentin and cystatin S expression, an indicator of HSG differentiation. HSG differentiation was also associated with Notch downstream signal Hes-1 expression, and Hes-1 expression was inhibited by ,-secretase inhibitors. siRNA corresponding to Notch 1 to 4 was used to show that silencing of all four Notch receptors was required to inhibit HSG differentiation. Normal human submandibular gland expressed Notch 1 to 4, Jagged 1 and 2, and Delta 1, with nuclear localization indicating Notch signaling in vivo. Hes-1 was also expressed in the human tissue, with staining predominantly in the ductal cells. In salivary tissue from rats undergoing and recovering from ductal obstruction, we found that Notch receptors and ligands were expressed in the nucleus of the regenerating epithelial cells. Taken together, these data suggest that Notch signaling is critical for normal salivary gland cell growth and differentiation. Developmental Dynamics 238:724,731, 2009. © 2009 Wiley-Liss, Inc. [source] In silico prediction and screening of ,-secretase inhibitors by molecular descriptors and machine learning methodsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 6 2010Xue-Gang Yang Abstract ,-Secretase inhibitors have been explored for the prevention and treatment of Alzheimer's disease (AD). Methods for prediction and screening of ,-secretase inhibitors are highly desired for facilitating the design of novel therapeutic agents against AD, especially when incomplete knowledge about the mechanism and three-dimensional structure of ,-secretase. We explored two machine learning methods, support vector machine (SVM) and random forest (RF), to develop models for predicting ,-secretase inhibitors of diverse structures. Quantitative analysis of the receiver operating characteristic (ROC) curve was performed to further examine and optimize the models. Especially, the Youden index (YI) was initially introduced into the ROC curve of RF so as to obtain an optimal threshold of probability for prediction. The developed models were validated by an external testing set with the prediction accuracies of SVM and RF 96.48 and 98.83% for ,-secretase inhibitors and 98.18 and 99.27% for noninhibitors, respectively. The different feature selection methods were used to extract the physicochemical features most relevant to ,-secretase inhibition. To the best of our knowledge, the RF model developed in this work is the first model with a broad applicability domain, based on which the virtual screening of ,-secretase inhibitors against the ZINC database was performed, resulting in 368 potential hit candidates. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010 [source] The cytoplasmic sequence of E-cadherin promotes non-amyloidogenic degradation of A, precursorsJOURNAL OF NEUROCHEMISTRY, Issue 4 2006Georgia Agiostratidou Abstract The presenilin (PS)/,-secretase system promotes production of the Abeta (A,) peptides by mediating cleavage of amyloid precursor protein (APP) at the ,-sites. This system is also involved in the processing of type-I transmembrane proteins, including APP, cadherins and Notch1 receptors, at the ,-cleavage site, resulting in the production of peptides containing the intracellular domains (ICDs) of the cleaved proteins. Emerging evidence shows that these peptides have important biological functions, raising the possibility that their inhibition by ,-secretase inhibitors may be detrimental to the cell. Here, we show that peptide E-Cad/CTF2, produced by the PS1/,-secretase processing of E-cadherin, promotes the lysosomal/endosomal degradation of the transmembrane APP derivatives, C99 and C83, and inhibits production of the APP ICD (AICD). In addition, E-Cad/CTF2 decreases accumulation of total secreted A,. These data suggest a novel method to promote the non-amyloidogenic degradation of A, precursors and to inhibit A, production. [source] Boom in the development of non-peptidic ,-secretase (BACE1) inhibitors for the treatment of Alzheimer's diseaseMEDICINAL RESEARCH REVIEWS, Issue 2 2009Romano Silvestri Abstract ,-Amyloid cleaving enzyme-1 (BACE1) has become a significant target for the therapy of Alzheimer's disease. After the discovery of the first non-peptidomimetic ,-secretase inhibitors by Takeda Chemicals in 2001, several research teams focused on SAR development of these agents. The non-peptidic BACE1 inhibitors may potentially overcome the classical problems associated with the peptide structure of first generation, such as blood,brain barrier crossing, poor oral bioavailability and susceptibility to P-glycoprotein transport. In the past 6 years a boom in research of non-peptidic BACE1 inhibitors has disseminated findings over hundreds of publications and patents. The rapidly growing literature has been reviewed with particular emphasis on literature of pharmaceutical companies. © 2008 Wiley Periodicals, Inc. Med Res Rev, 29, No. 2, 295,338, 2009 [source] , -secretase inhibitors exerts antitumor activity via down-regulation of Notch and Nuclear factor kappa B in human tongue carcinoma cellsORAL DISEASES, Issue 6 2007J Yao Objective:, To investigate the effect of the , -secretase inhibitors (GSIs) on the growth of human tongue carcinoma cells and to provide the molecular mechanism for potential application of GSIs in the treatment of tongue carcinoma. Materials and methods:, Human tongue carcinoma Tca8113 cells were cultured with the GSI L-685 458. Cell growth was determined by the methylthiazole tetrazolium method. Cell cycle and apoptosis were analyzed by flow cytometry and/or confocal microscopy. RT-PCR and Western blot were employed to determine the intracellular expression levels. Nuclear factor kappa B (NF- ,B) activation was examined by electrophoretic mobility shift assay. Results:, L-685,458 dose-dependently inhibited the growth of human tongue carcinoma Tca8113 cells by inducing G0,G1 cell cycle arrest and apoptosis. The mRNA and protein levels of Hairy/Enhancer of Split-1, a target of Notch activation, were decreased dose-dependently by L-685,458. Furthermore, L-685,458 down-regulated cyclin D1, B-cell lymphocytic-leukemia proto-oncogene 2 and c-Myc expressions, which are regulated by the transcription factor NF- ,B. Coincident with this observation, L-685,458 induced a dose-dependent reduction of constitutive NF- ,B activation in Tca8113 cells. Conclusions:, The GSI L-685,458 may have a therapeutic value for the treatment of human tongue carcinoma. Moreover, the effects of L-685,458 in tumor inhibition may act partially via the modulation of Notch and NF- ,B. [source] REVIEW: ,-Secretase Inhibitors for the Treatment of Alzheimer's Disease: The Current StateCNS: NEUROSCIENCE AND THERAPEUTICS, Issue 5 2010Francesco Panza SUMMARY Aims: Drugs currently used for the treatment of Alzheimer's disease (AD) partially stabilize patients' symptoms without modifying disease progression. Brain accumulation of oligomeric species of ,-amyloid (A,) peptides, the principal components of senile plaques, is believed to play a crucial role in the development of AD. Based on this hypothesis, huge efforts are being spent to identify drugs able to interfere with proteases regulating A, formation from amyloid precursor protein (APP). This article briefly reviews the profile of ,-secretase inhibitors, compounds that inhibit ,-secretase, the pivotal enzyme that generates A,, and that have reached the clinic. Discussion: Several classes of potent ,-secretase inhibitors have been designed and synthesized. Preclinical studies have indicated that these compounds are able to lower brain A, concentrations and, in some cases, reduce A, plaque deposition in transgenic mouse models of AD. The most developmentally advanced of these compounds is semagacestat, presently in Phase III clinical trials. In animals, semagacestat reduced A, levels in the plasma, cerebrospinal fluid (CSF), and the brain. However, studies have not reported on its cognitive effects. Studies in both healthy volunteers and patients with AD have demonstrated a dose-dependent inhibition of plasma A, levels, and a recent study in healthy subjects demonstrated a robust, dose-dependent inhibition of newly generated A, in the CSF after single oral doses. Conclusions: Unfortunately, ,-secretase inhibitors may cause intestinal goblet cell hyperplasia, thymus atrophy, decrease in lymphocytes, and alterations in hair color, effects associated with the inhibition of the cleavage of Notch, a protein involved in cell development and differentiation. Nevertheless, at least other two promising ,-secretase inhibitors are being tested clinically. This class of drugs represents a major hope to slow the rate of decline of AD. [source] | ||||||||||||||||