Base de dados : MEDLINE
Pesquisa : D03.633.100 [Categoria DeCS]
Referências encontradas : 696 [refinar]
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[PMID]:29278948
[Au] Autor:Nocentini A; Cadoni R; Dumy P; Supuran CT; Winum JY
[Ad] Endereço:a Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS, ENSCM, Université de Montpellier , Montpellier Cedex , France.
[Ti] Título:Carbonic anhydrases from Trypanosoma cruzi and Leishmania donovani chagasi are inhibited by benzoxaboroles.
[So] Source:J Enzyme Inhib Med Chem;33(1):286-289, 2018 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A series of 6-substituted ureido- and thioureido-benzoxaboroles were investigated as inhibitors of carbonic anhydrases from Trypanosoma cruzi (TcCA), and Leishmania donovani chagasi (LdcCA). Both enzymes were inhibited by benzoxaboroles in the micromolar range. Preferential inhibitory potency against the ß-CA LdcCA versus the α-CA TcCA was observed with submicromolar inhibitory activities. Some derivatives displayed excellent inhibitory and selectivity profile over the ubiquitous and physiological relevant human off-target hCA II. This study provides a convincing opportunity to study benzoxaborole scaffold for the design of antiprotozoan potential drugs targeting the pathogen's carbonic anhydrases.
[Mh] Termos MeSH primário: Antiprotozoários/farmacologia
Compostos de Boro/farmacologia
Inibidores da Anidrase Carbônica/farmacologia
Anidrases Carbônicas/metabolismo
Compostos Heterocíclicos com 2 Anéis/farmacologia
Leishmania donovani/efeitos dos fármacos
Trypanosoma cruzi/efeitos dos fármacos
[Mh] Termos MeSH secundário: Antiprotozoários/síntese química
Antiprotozoários/química
Compostos de Boro/síntese química
Compostos de Boro/química
Inibidores da Anidrase Carbônica/síntese química
Inibidores da Anidrase Carbônica/química
Relação Dose-Resposta a Droga
Compostos Heterocíclicos com 2 Anéis/síntese química
Compostos Heterocíclicos com 2 Anéis/química
Leishmania donovani/enzimologia
Testes de Sensibilidade Microbiana
Estrutura Molecular
Relação Estrutura-Atividade
Trypanosoma cruzi/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiprotozoal Agents); 0 (Boron Compounds); 0 (Carbonic Anhydrase Inhibitors); 0 (Heterocyclic Compounds, 2-Ring); EC 4.2.1.1 (Carbonic Anhydrases)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180105
[Lr] Data última revisão:
180105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171228
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2017.1414808


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[PMID]:28456553
[Au] Autor:Cheng W; Liu Z; Yu Y; van Ofwegen L; Proksch P; Yu S; Lin W
[Ad] Endereço:State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China.
[Ti] Título:An unusual spinaceamine-bearing pregnane from a soft coral Scleronephthya sp. inhibits the migration of tumor cells.
[So] Source:Bioorg Med Chem Lett;27(12):2736-2741, 2017 06 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:An unprecedented spinaceamine-bearing pregnane namely scleronine (1) was isolated from a Chinese soft coral Scleronephthya sp. Its structure was determined on the basis of 1D and 2D NMR spectroscopic analyses in association with the HRESIMS data, while the absolute configurations were deduced by the single-crystal X-ray diffraction analysis. In addition, a dehydrogenated analogue (3) was synthesized through six steps with pregna-1,20-dien-3-one (2) as a precursor. The significantly inhibitory effects of 1 and 3 against the migration of tumor cells A549 and B16 accompanying the down-regulation of key genes (TGFß, TNFα, IL-1ß, and IL-6) were observed. These findings suggested that both 1 and 3 are potential for therapeutic usage aiming at cancer metastasis inhibition.
[Mh] Termos MeSH primário: Antozoários/química
Compostos Heterocíclicos com 2 Anéis/farmacologia
Pregnanos/farmacologia
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Compostos Heterocíclicos com 2 Anéis/química
Compostos Heterocíclicos com 2 Anéis/isolamento & purificação
Seres Humanos
Estrutura Molecular
Pregnanos/química
Pregnanos/isolamento & purificação
Teoria Quântica
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Heterocyclic Compounds, 2-Ring); 0 (Pregnanes); 0 (scleronine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170501
[St] Status:MEDLINE


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[PMID]:29061802
[Au] Autor:Shiratori E; Itoh M; Tohda S
[Ad] Endereço:Department of Laboratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
[Ti] Título:MYD88 Inhibitor ST2825 Suppresses the Growth of Lymphoma and Leukaemia Cells.
[So] Source:Anticancer Res;37(11):6203-6209, 2017 11.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: Myeloid differentiation primary response gene 88 (MYD88), which activates the nuclear factor kappa B (NF-κB) pathway, is important for the growth of lymphoma and leukaemia cells. In this study, we investigated the effects of ST2825, a synthetic peptidomimetic compound which inhibits MYD88 homodimerization, on their growth. MATERIALS AND METHODS: Seven lymphoma and leukaemia cell lines including TMD8, a B-cell lymphoma line with MYD88-activating mutation, were treated with ST2825 and analysed for cell proliferation and expression of NF-κB signalling-related molecules. RESULTS: ST2825 suppressed the growth of all cell lines by inducing apoptosis and down-regulating phosphorylation of NF-κB pathway components inhibitor of nuclear factor kappa B kinase (IκB) and reticuloendotheliosis oncogene A (RelA), as well as of MYD88 activator Bruton tyrosine kinase (BTK), suggesting that MYD88 may affect BTK activity. ST2825 effects were specific as MYD88-targeting siRNA also suppressed phosphorylation of NF-κB signalling proteins and BTK in TMD8 cells. CONCLUSION: ST2825 may be a novel drug targeting not only B-lymphoid malignancies with MYD88 mutations, but also lymphoma and leukaemia with wild-type MYD88.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Compostos Heterocíclicos com 2 Anéis/farmacologia
Leucemia/patologia
Linfoma/patologia
Fator 88 de Diferenciação Mieloide/antagonistas & inibidores
Compostos de Espiro/farmacologia
[Mh] Termos MeSH secundário: Seres Humanos
Leucemia/tratamento farmacológico
Leucemia/metabolismo
Linfoma/tratamento farmacológico
Linfoma/metabolismo
Fator 88 de Diferenciação Mieloide/metabolismo
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Heterocyclic Compounds, 2-Ring); 0 (MYD88 protein, human); 0 (Myeloid Differentiation Factor 88); 0 (ST2825); 0 (Spiro Compounds)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171025
[St] Status:MEDLINE


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[PMID]:29061784
[Au] Autor:Ohtaka M; Itoh M; Tohda S
[Ad] Endereço:Department of Laboratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
[Ti] Título:BMI1 Inhibitors Down-regulate NOTCH Signaling and Suppress Proliferation of Acute Leukemia Cells.
[So] Source:Anticancer Res;37(11):6047-6053, 2017 11.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: B cell-specific Moloney murine leukemia virus integration site 1 (BMI1) is up-regulated in several cancers; therefore, we investigated the effects of BMI1 inhibitors on leukemia cells. MATERIALS AND METHODS: Four acute myeloid leukemia and two T-lymphoblastic leukemia cell lines were treated with BMI1 inhibitors artemisinin, PRT4165, and PTC-209 and analyzed for cell proliferation and gene expression by microarray and immunoblotting. RESULTS: PTC-209 and PRT4165 suppressed the growth of all cell lines through apoptosis.Artemisinin acted only on Jurkat cells. BMI1 inhibitors and BMI1-specific siRNA down-regulated the expression of NOTCH signaling proteins NOTCH1, HES1, and MYC. All but one cell lines did not have the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene targeted by BMI1, thus the inhibitors acted through CDKN2A-independent pathways. CONCLUSION: BMI1 inhibition suppressed proliferation of leukemia cells through NOTCH signaling which functions downstream of BMI1, suggesting that BMI1 inhibitors can be candidate targeted drugs against leukemia.
[Mh] Termos MeSH primário: Proliferação Celular/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Compostos Heterocíclicos com 2 Anéis/farmacologia
Leucemia Mieloide Aguda/patologia
Leucemia de Células T/patologia
Complexo Repressor Polycomb 1/antagonistas & inibidores
Receptores Notch/antagonistas & inibidores
Tiazóis/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Seres Humanos
Leucemia Mieloide Aguda/tratamento farmacológico
Leucemia Mieloide Aguda/metabolismo
Leucemia de Células T/tratamento farmacológico
Leucemia de Células T/metabolismo
Complexo Repressor Polycomb 1/genética
Complexo Repressor Polycomb 1/metabolismo
RNA Interferente Pequeno/genética
Receptores Notch/genética
Receptores Notch/metabolismo
Transdução de Sinais/efeitos dos fármacos
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BMI1 protein, human); 0 (Heterocyclic Compounds, 2-Ring); 0 (PTC-209); 0 (RNA, Small Interfering); 0 (Receptors, Notch); 0 (Thiazoles); EC 2.3.2.27 (Polycomb Repressive Complex 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171025
[St] Status:MEDLINE


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[PMID]:28953378
[Au] Autor:Li X; Hernandez V; Rock FL; Choi W; Mak YSL; Mohan M; Mao W; Zhou Y; Easom EE; Plattner JJ; Zou W; Pérez-Herrán E; Giordano I; Mendoza-Losana A; Alemparte C; Rullas J; Angulo-Barturen I; Crouch S; Ortega F; Barros D; Alley MRK
[Ad] Endereço:Anacor Pharmaceuticals, Inc. , 1020 E. Meadow Circle, Palo Alto, California 94303, United States.
[Ti] Título:Discovery of a Potent and Specific M. tuberculosis Leucyl-tRNA Synthetase Inhibitor: (S)-3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol (GSK656).
[So] Source:J Med Chem;60(19):8011-8026, 2017 Oct 12.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:There is an urgent need to develop new and safer antitubercular agents that possess a novel mode of action. We synthesized and evaluated a novel series of 3-aminomethyl 4-halogen benzoxaboroles as Mycobacterium tuberculosis (Mtb) leucyl-tRNA synthetase (LeuRS) inhibitors. A number of Mtb LeuRS inhibitors were identified that demonstrated good antitubercular activity with high selectivity over human mitochondrial and cytoplasmic LeuRS. Further evaluation of these Mtb LeuRS inhibitors by in vivo pharmacokinetics (PK) and murine tuberculosis (TB) efficacy models led to the discovery of GSK3036656 (abbreviated as GSK656). This molecule shows potent inhibition of Mtb LeuRS (IC = 0.20 µM) and in vitro antitubercular activity (Mtb H37Rv MIC = 0.08 µM). Additionally, it is highly selective for the Mtb LeuRS enzyme with IC of >300 µM and 132 µM for human mitochondrial LeuRS and human cytoplasmic LeuRS, respectively. In addition, it exhibits remarkable PK profiles and efficacy against Mtb in mouse TB infection models with superior tolerability over initial leads. This compound has been progressed to clinical development for the treatment of tuberculosis.
[Mh] Termos MeSH primário: Antituberculosos/síntese química
Antituberculosos/farmacologia
Compostos de Boro/farmacologia
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/farmacologia
Compostos Heterocíclicos com 2 Anéis/farmacologia
Leucina-tRNA Ligase/antagonistas & inibidores
Mycobacterium tuberculosis/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Antituberculosos/farmacocinética
Compostos de Boro/síntese química
Compostos de Boro/farmacocinética
Descoberta de Drogas
Inibidores Enzimáticos/farmacocinética
Feminino
Compostos Heterocíclicos com 2 Anéis/síntese química
Seres Humanos
Camundongos
Camundongos Endogâmicos C57BL
Mycobacterium tuberculosis/enzimologia
Relação Estrutura-Atividade
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antitubercular Agents); 0 (Boron Compounds); 0 (Enzyme Inhibitors); 0 (GSK656); 0 (Heterocyclic Compounds, 2-Ring); EC 6.1.1.4 (Leucine-tRNA Ligase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170928
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00631


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[PMID]:28927787
[Au] Autor:Ueda H; Kurita JI; Neyama H; Hirao Y; Kouji H; Mishina T; Kasai M; Nakano H; Yoshimori A; Nishimura Y
[Ad] Endereço:Department of Pharmacology and Therapeutic Innovation, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8521, Japan.
[Ti] Título:A mimetic of the mSin3-binding helix of NRSF/REST ameliorates abnormal pain behavior in chronic pain models.
[So] Source:Bioorg Med Chem Lett;27(20):4705-4709, 2017 10 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The neuron-restrictive silencing factor NRSF/REST binds to neuron-restrictive silencing elements in neuronal genes and recruits corepressors such as mSin3 to inhibit epigenetically neuronal gene expression. Because dysregulation of NRSF/REST is related to neuropathic pain, here, we have designed compounds to target neuropathic pain based on the mSin3-binding helix structure of NRSF/REST and examined their ability to bind to mSin3 by NMR. One compound, mS-11, binds strongly to mSin3 with a binding mode similar to that of NRSF/REST. In a mouse model of neuropathic pain, mS-11 was found to ameliorate abnormal pain behavior and to reverse lost peripheral morphine analgesia. Furthermore, even in the less well epigenetically defined case of fibromyalgia, mS-11 ameliorated symptoms in a mouse model, suggesting that fibromyalgia is related to the dysfunction of NRSF/REST. Taken together, these findings show that the chemically optimized mimetic mS-11 can inhibit mSin3-NRSF/REST binding and successfully reverse lost peripheral and central morphine analgesia in mouse models of pain.
[Mh] Termos MeSH primário: Proteínas de Transporte/metabolismo
Dor Crônica/tratamento farmacológico
Compostos Heterocíclicos com 2 Anéis/metabolismo
Proteínas Repressoras/metabolismo
[Mh] Termos MeSH secundário: Analgésicos Opioides/uso terapêutico
Animais
Sítios de Ligação
Proteínas de Transporte/química
Dor Crônica/patologia
Temperatura Baixa
Modelos Animais de Doenças
Compostos Heterocíclicos com 2 Anéis/química
Compostos Heterocíclicos com 2 Anéis/uso terapêutico
Camundongos
Simulação de Acoplamento Molecular
Morfina/uso terapêutico
Neuralgia/tratamento farmacológico
Neuralgia/patologia
Ligação Proteica
Domínios Proteicos
Estrutura Secundária de Proteína
Proteínas Repressoras/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Analgesics, Opioid); 0 (Carrier Proteins); 0 (Heterocyclic Compounds, 2-Ring); 0 (MS-11 compound); 0 (RE1-silencing transcription factor); 0 (Repressor Proteins); 76I7G6D29C (Morphine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170921
[St] Status:MEDLINE


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[PMID]:28592427
[Au] Autor:Mattila JT; Beaino W; Maiello P; Coleman MT; White AG; Scanga CA; Flynn JL; Anderson CJ
[Ad] Endereço:Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15213.
[Ti] Título:Positron Emission Tomography Imaging of Macaques with Tuberculosis Identifies Temporal Changes in Granuloma Glucose Metabolism and Integrin α4ß1-Expressing Immune Cells.
[So] Source:J Immunol;199(2):806-815, 2017 Jul 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Positron emission tomography and computed tomography imaging (PET/CT) is an increasingly valuable tool for diagnosing tuberculosis (TB). The glucose analog [ F]fluoro-2-deoxy-2-d-glucose ([ F]-FDG) is commonly used in PET/CT that is retained by metabolically active inflammatory cells in granulomas, but lacks specificity for particular cell types. A PET probe that could identify recruitment and differentiation of different cell populations in granulomas would be a useful research tool and could improve TB diagnosis and treatment. We used the -antigen murine inflammation model and macaques with TB to identify [ Cu]-labeled CB-TE1A1P-PEG -LLP2A ([ Cu]-LLP2A), a high affinity peptidomimetic ligand for very late Ag-4 (VLA-4; also called integrin α4ß1) binding cells in granulomas, and compared [ Cu]-LLP2A with [ F]-FDG over the course of infection. We found that [ Cu]-LLP2A retention was driven by macrophages and T cells, with less contribution from neutrophils and B cells. In macaques, granulomas had higher [ Cu]-LLP2A uptake than uninfected tissues, and immunohistochemical analysis of granulomas with known [ Cu]-LLP2A uptake identified significant correlations between LLP2A signal and macrophage and T cell numbers. The same cells coexpressed integrin α4 and ß1, further supporting that macrophages and T cells drive [ Cu]-LLP2A avidity in granulomas. Over the course of infection, granulomas and thoracic lymph nodes experienced dynamic changes in affinity for both probes, suggesting metabolic changes and cell differentiation or recruitment occurs throughout granuloma development. These results indicate [ Cu]-LLP2A is a PET probe for VLA-4, which when used in conjunction with [ F]-FDG, may be a useful tool for understanding granuloma biology in TB.
[Mh] Termos MeSH primário: Glucose/metabolismo
Granuloma/imunologia
Integrina alfa4beta1/genética
Tuberculose/diagnóstico por imagem
Tuberculose/imunologia
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular
Movimento Celular
Granuloma/diagnóstico por imagem
Granuloma/metabolismo
Granuloma/fisiopatologia
Compostos Heterocíclicos com 2 Anéis/química
Integrina alfa4beta1/imunologia
Linfonodos/citologia
Linfonodos/imunologia
Macaca
Macrófagos/imunologia
Neutrófilos/imunologia
Organofosfonatos/química
Tomografia Computadorizada com Tomografia por Emissão de Pósitrons
Compostos Radiofarmacêuticos
Linfócitos T/imunologia
Tuberculose/diagnóstico
Tuberculose/microbiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1,4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methane carboxylic acid)); 0 (Heterocyclic Compounds, 2-Ring); 0 (Integrin alpha4beta1); 0 (Organophosphonates); 0 (Radiopharmaceuticals); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170928
[Lr] Data última revisão:
170928
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170609
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700231


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[PMID]:28557445
[Au] Autor:Follmann M; Ackerstaff J; Redlich G; Wunder F; Lang D; Kern A; Fey P; Griebenow N; Kroh W; Becker-Pelster EM; Kretschmer A; Geiss V; Li V; Straub A; Mittendorf J; Jautelat R; Schirok H; Schlemmer KH; Lustig K; Gerisch M; Knorr A; Tinel H; Mondritzki T; Trübel H; Sandner P; Stasch JP
[Ad] Endereço:Drug Discovery, Bayer AG , Aprather Weg 18a, 42113 Wuppertal, Germany.
[Ti] Título:Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure.
[So] Source:J Med Chem;60(12):5146-5161, 2017 Jun 22.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The first-in-class soluble guanylate cyclase (sGC) stimulator riociguat was recently introduced as a novel treatment option for pulmonary hypertension. Despite its outstanding pharmacological profile, application of riociguat in other cardiovascular indications is limited by its short half-life, necessitating a three times daily dosing regimen. In our efforts to further optimize the compound class, we have uncovered interesting structure-activity relationships and were able to decrease oxidative metabolism significantly. These studies resulting in the discovery of once daily sGC stimulator vericiguat (compound 24, BAY 1021189), currently in phase 3 trials for chronic heart failure, are now reported.
[Mh] Termos MeSH primário: Insuficiência Cardíaca/tratamento farmacológico
Compostos Heterocíclicos com 2 Anéis/química
Compostos Heterocíclicos com 2 Anéis/farmacologia
Pirimidinas/química
Pirimidinas/farmacologia
Guanilil Ciclase Solúvel/metabolismo
Relação Estrutura-Atividade
[Mh] Termos MeSH secundário: Administração Intravenosa
Administração Oral
Animais
Pressão Sanguínea/efeitos dos fármacos
Técnicas de Química Sintética
Cães
Hepatócitos/efeitos dos fármacos
Compostos Heterocíclicos com 2 Anéis/administração & dosagem
Seres Humanos
Masculino
NG-Nitroarginina Metil Éster/efeitos adversos
Pirimidinas/administração & dosagem
Ratos Transgênicos
Ratos Wistar
Guanilil Ciclase Solúvel/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Heterocyclic Compounds, 2-Ring); 0 (Pyrimidines); 0 (vericiguat); EC 4.6.1.2 (Soluble Guanylyl Cyclase); V55S2QJN2X (NG-Nitroarginine Methyl Ester)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170811
[Lr] Data última revisão:
170811
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170531
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00449


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[PMID]:28529112
[Au] Autor:Wang N; Han X; Liu H; Zhao T; Li J; Feng Y; Mi X; Zhang Y; Chen Y; Wang X
[Ad] Endereço:Department of Neurology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou 450003, China; Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing 400016, China.
[Ti] Título:Myeloid differentiation factor 88 is up-regulated in epileptic brain and contributes to experimental seizures in rats.
[So] Source:Exp Neurol;295:23-35, 2017 Sep.
[Is] ISSN:1090-2430
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Accumulating evidence supports that activation of inflammatory pathways is a crucial factor contributing to the pathogenesis of seizures. In particular, the activation of interleukin-1 beta (IL-1ß) system exerts proconvulsant effects in a large variety of seizure models. Myeloid differentiation factor 88 (MyD88) is a critical adaptor protein in the signaling cascade elicited by IL-1ß. The present study aimed to investigate the expression pattern of MyD88 in rat models of seizures and in patients with refractory temporal lobe epilepsy (TLE), and to study the role of MyD88 in epileptic seizures. Our results revealed that MyD88 was up-regulated in the hippocampus of rats in the lithium-pilocarpine model of acute seizures. Importantly, MyD88 overexpression was also significantly present in the brain from chronic epileptic rats and the temporal neocortex specimens from drug-resistant TLE patients. In the acute seizure model, both the behavioral and electrographic seizure activities were record and analyzed in rats for 90min, starting immediately after pilocarpine injection. ST2825, a synthetic MyD88 inhibitor, was administered intracerebroventricularly (2.5-5.0-10µg in 2µl) 20min before pilocarpine injection. We found that ST2825 at doses of 5µg and 10µg significantly inhibited the pilocarpine-induced behavioral and electrographic seizures. Moreover, 10µg ST2825 prevented the proconvulsant actions of IL-1ß. As previous evidence suggested that IL-1ß proconvulsant effects was mediated by enhancing the phosphorylation level of the NR2B subunit of N-methyl-d-aspartate (NMDA) receptor, we then probed whether this molecular was involved in the effect of the pharmacological inhibition. Our results revealed that 10µg ST2825 markedly reversed the increased Tyr -phosphorylation of the NR2B subunit of NMDA receptor observed in the proconvulsant conditions of IL-1ß and in seizures induced by pilocarpine alone. These findings indicate that altered expression of MyD88 might contribute to the pathogenesis of seizures and targeting of this adaptor protein might represent a novel therapeutic strategy to suppress seizure activities.
[Mh] Termos MeSH primário: Epilepsia/genética
Epilepsia/fisiopatologia
Fator 88 de Diferenciação Mieloide/biossíntese
Fator 88 de Diferenciação Mieloide/genética
Convulsões/genética
Convulsões/fisiopatologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Animais
Anticonvulsivantes/farmacologia
Convulsivantes
Eletroencefalografia/efeitos dos fármacos
Epilepsia/induzido quimicamente
Epilepsia do Lobo Temporal/genética
Epilepsia do Lobo Temporal/metabolismo
Epilepsia do Lobo Temporal/fisiopatologia
Feminino
Compostos Heterocíclicos com 2 Anéis/antagonistas & inibidores
Compostos Heterocíclicos com 2 Anéis/farmacologia
Seres Humanos
Injeções Intraventriculares
Interleucina-1beta/antagonistas & inibidores
Interleucina-1beta/farmacologia
Masculino
Meia-Idade
Fator 88 de Diferenciação Mieloide/antagonistas & inibidores
Pilocarpina
Ratos
Ratos Sprague-Dawley
Receptores de N-Metil-D-Aspartato/metabolismo
Convulsões/induzido quimicamente
Compostos de Espiro/antagonistas & inibidores
Compostos de Espiro/farmacologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticonvulsants); 0 (Convulsants); 0 (Heterocyclic Compounds, 2-Ring); 0 (Interleukin-1beta); 0 (MYD88 protein, human); 0 (Myd88 protein, rat); 0 (Myeloid Differentiation Factor 88); 0 (NR2B NMDA receptor); 0 (Receptors, N-Methyl-D-Aspartate); 0 (ST2825); 0 (Spiro Compounds); 01MI4Q9DI3 (Pilocarpine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170523
[St] Status:MEDLINE


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[PMID]:28492317
[Au] Autor:Tamanini E; Buck IM; Chessari G; Chiarparin E; Day JEH; Frederickson M; Griffiths-Jones CM; Hearn K; Heightman TD; Iqbal A; Johnson CN; Lewis EJ; Martins V; Peakman T; Reader M; Rich SJ; Ward GA; Williams PA; Wilsher NE
[Ad] Endereço:Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
[Ti] Título:Discovery of a Potent Nonpeptidomimetic, Small-Molecule Antagonist of Cellular Inhibitor of Apoptosis Protein 1 (cIAP1) and X-Linked Inhibitor of Apoptosis Protein (XIAP).
[So] Source:J Med Chem;60(11):4611-4625, 2017 Jun 08.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:XIAP and cIAP1 are members of the inhibitor of apoptosis protein (IAP) family and are key regulators of anti-apoptotic and pro-survival signaling pathways. Overexpression of IAPs occurs in various cancers and has been associated with tumor progression and resistance to treatment. Structure-based drug design (SBDD) guided by structural information from X-ray crystallography, computational studies, and NMR solution conformational analysis was successfully applied to a fragment-derived lead resulting in AT-IAP, a potent, orally bioavailable, dual antagonist of XIAP and cIAP1 and a structurally novel chemical probe for IAP biology.
[Mh] Termos MeSH primário: Compostos Heterocíclicos com 2 Anéis/química
Compostos Heterocíclicos com 2 Anéis/farmacologia
Proteínas Inibidoras de Apoptose/antagonistas & inibidores
Piperazinas/química
Piperazinas/farmacologia
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Cristalografia por Raios X
Descoberta de Drogas
Células HEK293
Seres Humanos
Camundongos
Camundongos Endogâmicos BALB C
Camundongos SCID
Peptidomiméticos
Bibliotecas de Moléculas Pequenas
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AT-IAP compound); 0 (Heterocyclic Compounds, 2-Ring); 0 (Inhibitor of Apoptosis Proteins); 0 (Peptidomimetics); 0 (Piperazines); 0 (Small Molecule Libraries); 0 (X-Linked Inhibitor of Apoptosis Protein); 0 (XIAP protein, human)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170704
[Lr] Data última revisão:
170704
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170512
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.6b01877



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