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[PMID]:28855109
[Au] Autor:Li H; Kim HW; Shin SE; Seo MS; An JR; Ha KS; Han ET; Hong SH; Firth AL; Choi IW; Han IY; Lee DS; Yim MJ; Park WS
[Ad] Endereço:Department of Physiology, Kangwon National University School of Medicine, Chuncheon 24341, South Korea.
[Ti] Título:The vasorelaxant effect of mitiglinide via activation of voltage-dependent K channels and SERCA pump in aortic smooth muscle.
[So] Source:Life Sci;188:1-9, 2017 Nov 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: The vasorelaxant effects of the anti-diabetic drug, mitiglinide in phenylephrine (Phe)-pre-contracted aortic rings were examined. MATERIALS AND METHODS: Arterial tone measurement was performed in aortic smooth muscle cells. KEY FINDINGS: Mitiglinide dose-dependently induced vasorelaxation. Application of the large-conductance Ca -activated K (BK ) channel blocker paxilline, inwardly rectifying K (Kir) channel blocker Ba , and ATP-sensitive K (K ) channel blocker glibenclamide did not affect the vasorelaxant effect of mitiglinide. However, application of the voltage-dependent K (Kv) channel blocker 4-AP, effectively inhibited mitiglinide-induced vasorelaxation. Although pretreatment with the Ca channel blocker nifedipine did not alter the mitiglinide-induced vasorelaxation, pretreatment with the sarcoplasmic/endoplasmic reticulum Ca -ATPase (SERCA) pump inhibitor thapsigargin and cyclopiazonic acid reduced the vasorelaxant effect of mitiglinide. In addition, the vasorelaxant effect of mitiglinide was not affected by the inhibitors of adenylyl cyclase, protein kinase A, guanylyl cyclase, or protein kinase G. Elimination of the endothelium and inhibition of endothelium-dependent vasorelaxant mechanisms also did not change the vasorelaxant effect of mitiglinide. SIGNIFICANCE: We proposed that mitiglinide induces vasorelaxation via activation of Kv channels and SERCA pump. However, the vasorelaxant effects of mitiglinide did not involve other K channels, Ca channels, PKA/PKG signaling pathways, or the endothelium.
[Mh] Termos MeSH primário: Aorta Torácica/fisiologia
Isoindóis/farmacologia
Músculo Liso/fisiologia
Canais de Potássio de Abertura Dependente da Tensão da Membrana/agonistas
ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/fisiologia
Vasodilatadores/farmacologia
[Mh] Termos MeSH secundário: 4-Aminopiridina/farmacologia
Adenina/análogos & derivados
Adenina/farmacologia
Animais
Aorta Torácica/efeitos dos fármacos
Bário/farmacologia
Carbazóis/farmacologia
Relação Dose-Resposta a Droga
Interações Medicamentosas
Endotélio Vascular/efeitos dos fármacos
Glibureto/farmacologia
Indóis/farmacologia
Isoindóis/antagonistas & inibidores
Masculino
Músculo Liso/efeitos dos fármacos
Nifedipino/farmacologia
Oxidiazóis/farmacologia
Fenilefrina/farmacologia
Pirróis/farmacologia
Quinoxalinas/farmacologia
Coelhos
ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores
Transdução de Sinais/efeitos dos fármacos
Tapsigargina/farmacologia
Vasodilatadores/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one); 0 (Carbazoles); 0 (Indoles); 0 (Isoindoles); 0 (Oxadiazoles); 0 (Potassium Channels, Voltage-Gated); 0 (Pyrroles); 0 (Quinoxalines); 0 (Vasodilator Agents); 126643-37-6 (KT 5823); 17318-31-9 (9-(tetrahydro-2-furyl)-adenine); 1WS297W6MV (Phenylephrine); 24GP945V5T (Barium); 3T9U9Z96L7 (paxilline); 58HV29I28S (KT 5720); 67526-95-8 (Thapsigargin); BH3B64OKL9 (4-Aminopyridine); D86I0XLB13 (mitiglinide); EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases); I9ZF7L6G2L (Nifedipine); JAC85A2161 (Adenine); SX6K58TVWC (Glyburide); X9TLY4580Z (cyclopiazonic acid)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE


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[PMID]:28768933
[Au] Autor:Kimuro Y; Usui K; Karasawa S; Hirai G; Aso M
[Ad] Endereço:Graduate School of Pharmaceutical Sciences, Kyushu University.
[Ti] Título:7-Hydroxy-3-methyleneisoindolin-1-one as a New ESIPT-Fluorescent Probe to Monitor Aqueous Environments.
[So] Source:Chem Pharm Bull (Tokyo);65(8):796-800, 2017.
[Is] ISSN:1347-5223
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:A 7-hydroxy derivative of 3-methyleneisoindolin-1-one 1 was synthesized and its properties as a new fluorophore undergoing excited-state intramolecular proton transfer (ESIPT) were investigated. In alcohols and dimethylsulfoxide, 1 exhibited dual emission at ca. 380 and 525-540 nm when excited at ca. 336 nm, which agreed well with the density functional theory (DFT) and time-dependent (TD)-DFT-calculated emission predictions of 1 and its ESIPT tautomer. In aqueous solutions at near neutral pH, 1 exhibited a broad emission band at ca. 497 nm, presumably caused by the overlap of emissions from 1 and the excited state phenolate species of 1. In binary mixtures of H O and EtOH, the wavelength and intensity of fluorescence maxima were dependent on the dielectric constant of the solvent, suggesting that 1 could be applied as a fluorescent probe to monitor aqueous environments.
[Mh] Termos MeSH primário: Corantes Fluorescentes/análise
Corantes Fluorescentes/química
Isoindóis/química
Prótons
Água/química
[Mh] Termos MeSH secundário: Corantes Fluorescentes/síntese química
Isoindóis/síntese química
Estrutura Molecular
Teoria Quântica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (7-hydroxy-3-methyleneisoindolin-1-one); 0 (Fluorescent Dyes); 0 (Isoindoles); 0 (Protons); 059QF0KO0R (Water)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170829
[Lr] Data última revisão:
170829
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170804
[St] Status:MEDLINE
[do] DOI:10.1248/cpb.c17-00306


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[PMID]:28728105
[Au] Autor:Azimi S; Zonouzi A; Firuzi O; Iraji A; Saeedi M; Mahdavi M; Edraki N
[Ad] Endereço:School of Chemistry, College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran.
[Ti] Título:Discovery of imidazopyridines containing isoindoline-1,3-dione framework as a new class of BACE1 inhibitors: Design, synthesis and SAR analysis.
[So] Source:Eur J Med Chem;138:729-737, 2017 Sep 29.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Alzheimer's disease is characterized by chronic neurodegeneration leading to dementia. The main cause of neurodegeneration is considered to be the accumulation of amyloid-ß. Inhibiting BACE1 is a well-studied approach to lower the burden of amyloid-ß aggregates. We designed a series of imidazopyridines-based compounds bearing phthalimide moieties as inhibitors of BACE1. The compounds 8a-o were synthesized by the Groebke-Blackburn-Bienaymé three-component reaction of heteroaromatic amidines, aldehydes and isocyanides. Evaluating the BACE1 inhibitory effects of the synthesized compounds revealed that introducing an aminocyclohexyl moiety in the imidazopyridine core resulted in a significant improvement in its BACE1 inhibitory potential. In this regard, compound 8e was the most potent against BACE1 with an IC value of 2.84 (±0.95) µM. Molecular docking revealed that the nitrogen atom of imidazopyridines and the oxygen atom of the phenoxypropyl linker were involved in hydrogen bound interactions with Asp228 and Asp32 of BACE1 active site, respectively. The phthalimide moiety oriented toward the flap pocket and interacted with phe108, lle110, Trp115, Ile118 through van der Waal's and hydrophobic interactions. These findings demonstrate that imidazopyridines-based compounds bearing phthalimide moiety have the potential to decrease amyloid-ß levels and ameliorate the symptoms of Alzheimer's disease.
[Mh] Termos MeSH primário: Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores
Ácido Aspártico Endopeptidases/antagonistas & inibidores
Descoberta de Drogas
Imidazóis/farmacologia
Isoindóis/farmacologia
Inibidores de Proteases/farmacologia
Piridinas/farmacologia
[Mh] Termos MeSH secundário: Secretases da Proteína Precursora do Amiloide/metabolismo
Ácido Aspártico Endopeptidases/metabolismo
Relação Dose-Resposta a Droga
Seres Humanos
Imidazóis/síntese química
Imidazóis/química
Isoindóis/química
Estrutura Molecular
Inibidores de Proteases/síntese química
Inibidores de Proteases/química
Piridinas/síntese química
Piridinas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Imidazoles); 0 (Isoindoles); 0 (Protease Inhibitors); 0 (Pyridines); 0 (imidazopyridine); 0 (isoindoline-1,3-dione); EC 3.4.- (Amyloid Precursor Protein Secretases); EC 3.4.23.- (Aspartic Acid Endopeptidases); EC 3.4.23.46 (BACE1 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170721
[St] Status:MEDLINE


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[PMID]:28702990
[Au] Autor:Manchekar M; Kapil R; Sun Z; Segrest JP; Dashti N
[Ti] Título:Relationship between Amphipathic ß Structures in the ß Domain of Apolipoprotein B and the Properties of the Secreted Lipoprotein Particles in McA-RH7777 Cells.
[So] Source:Biochemistry;56(31):4084-4094, 2017 Aug 08.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Our previous studies demonstrated that the first 1000 amino acid residues (the ßα domain) of human apolipoprotein (apo) B-100, termed apoB:1000, are required for the initiation of lipoprotein assembly and the formation of a monodisperse stable phospholipid (PL)-rich particle. The objectives of this study were (a) to assess the effects on the properties of apoB truncates undergoing sequential inclusion of the amphipathic ß strands in the 700 N-terminal residues of the ß domain of apoB-100 and (b) to identify the subdomain in the ß domain that is required for the formation of a microsomal triglyceride transfer protein (MTP)-dependent triacylglycerol (TAG)-rich apoB-containing particle. Characterization of particles secreted by stable transformants of McA-RH7777 cells demonstrated the following. (1) The presence of amphipathic ß strands in the 200 N-terminal residues of the ß domain resulted in the secretion of apoB truncates (apoB:1050 to apoB:1200) as both lipidated and lipid-poor particles. (2) Inclusion of residues 300-700 of the ß domain led to the secretion of apoB:1300, apoB:1400, apoB:1500, and apoB:1700 predominantly as lipidated particles. (3) Particles containing residues 1050-1500 were all rich in PL. (4) There was a marked increase in the lipid loading capacity and TAG content of apoB:1700-containing particles. (5) Only the level of secretion of apoB:1700 was markedly diminished by MTP inhibitor BMS-197636. These results suggest that apoB:1700 marks the threshold for the formation of a TAG-rich particle and support the concept that MTP participates in apoB assembly and secretion at the stage where particles undergo a transition from PL-rich to TAG-rich.
[Mh] Termos MeSH primário: Apolipoproteína B-100/química
Proteínas de Transporte/metabolismo
Hepatócitos/secreção
Lipoproteínas VLDL/secreção
[Mh] Termos MeSH secundário: Animais
Apolipoproteína B-100/genética
Apolipoproteína B-100/metabolismo
Apolipoproteína B-100/secreção
Transporte Biológico/efeitos dos fármacos
Proteínas de Transporte/antagonistas & inibidores
Linhagem Celular Tumoral
Fluorenos/farmacologia
Hepatócitos/efeitos dos fármacos
Hepatócitos/metabolismo
Seres Humanos
Isoindóis/farmacologia
Lipoproteínas VLDL/antagonistas & inibidores
Lipoproteínas VLDL/química
Lipoproteínas VLDL/metabolismo
Peso Molecular
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Fragmentos de Peptídeos/secreção
Fosfolipídeos/análise
Fosfolipídeos/metabolismo
Fosfolipídeos/secreção
Conformação Proteica em alfa-Hélice
Conformação Proteica em Folha beta
Dobramento de Proteína
Domínios e Motivos de Interação entre Proteínas
Estabilidade Proteica
Proteólise/efeitos dos fármacos
Ratos
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Proteínas Recombinantes de Fusão/secreção
Triglicerídeos/análise
Triglicerídeos/metabolismo
Triglicerídeos/secreção
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (APOB protein, human); 0 (Apolipoprotein B-100); 0 (BMS 197636); 0 (Carrier Proteins); 0 (Fluorenes); 0 (Isoindoles); 0 (Lipoproteins, VLDL); 0 (Peptide Fragments); 0 (Phospholipids); 0 (Recombinant Fusion Proteins); 0 (Triglycerides); 0 (microsomal triglyceride transfer protein)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170714
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.6b01174


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[PMID]:28610984
[Au] Autor:Curtin ML; Heyman HR; Clark RF; Sorensen BK; Doherty GA; Hansen TM; Frey RR; Sarris KA; Aguirre AL; Shrestha A; Tu N; Woller K; Pliushchev MA; Sweis RF; Cheng M; Wilsbacher JL; Kovar PJ; Guo J; Cheng D; Longenecker KL; Raich D; Korepanova AV; Soni NB; Algire MA; Richardson PL; Marin VL; Badagnani I; Vasudevan A; Buchanan FG; Maag D; Chiang GG; Tse C; Michaelides MR
[Ad] Endereço:AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States. Electronic address: mike.curtin@abbvie.com.
[Ti] Título:SAR and characterization of non-substrate isoindoline urea inhibitors of nicotinamide phosphoribosyltransferase (NAMPT).
[So] Source:Bioorg Med Chem Lett;27(15):3317-3325, 2017 08 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.
[Mh] Termos MeSH primário: Antineoplásicos/química
Antineoplásicos/farmacologia
Citocinas/antagonistas & inibidores
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Nicotinamida Fosforribosiltransferase/antagonistas & inibidores
Ureia/análogos & derivados
Ureia/farmacologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/farmacocinética
Antineoplásicos/uso terapêutico
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Cristalografia por Raios X
Citocinas/química
Citocinas/metabolismo
Descoberta de Drogas
Inibidores Enzimáticos/farmacocinética
Inibidores Enzimáticos/uso terapêutico
Seres Humanos
Isoindóis/química
Isoindóis/farmacocinética
Isoindóis/farmacologia
Isoindóis/uso terapêutico
Camundongos
Modelos Moleculares
Neoplasias/tratamento farmacológico
Neoplasias/metabolismo
Neoplasias/patologia
Nicotinamida Fosforribosiltransferase/química
Nicotinamida Fosforribosiltransferase/metabolismo
Relação Estrutura-Atividade
Ureia/farmacocinética
Ureia/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Cytokines); 0 (Enzyme Inhibitors); 0 (Isoindoles); 8W8T17847W (Urea); EC 2.4.2.12 (Nicotinamide Phosphoribosyltransferase); EC 2.4.2.12 (nicotinamide phosphoribosyltransferase, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170615
[St] Status:MEDLINE


  6 / 1539 MEDLINE  
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[PMID]:28598634
[Au] Autor:Davoren JE; Garnsey M; Pettersen B; Brodney MA; Edgerton JR; Fortin JP; Grimwood S; Harris AR; Jenkinson S; Kenakin T; Lazzaro JT; Lee CW; Lotarski SM; Nottebaum L; O'Neil SV; Popiolek M; Ramsey S; Steyn SJ; Thorn CA; Zhang L; Webb D
[Ti] Título:Design and Synthesis of γ- and δ-Lactam M Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M -Selective PAM with Weak Agonist Activity.
[So] Source:J Med Chem;60(15):6649-6663, 2017 Aug 10.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recent data demonstrated that activation of the muscarinic M receptor by a subtype-selective positive allosteric modulator (PAM) contributes to the gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed to M and M activation. These studies were conducted using PAMs that also exhibited allosteric agonist activity, leaving open the possibility that direct activation by allosteric agonism, rather than allosteric modulation, could be responsible for the adverse effects. This article describes the design and synthesis of lactam-derived M PAMs that address this hypothesis. The lead molecule from this series, compound 1 (PF-06827443), is a potent, low-clearance, orally bioavailable, and CNS-penetrant M -selective PAM with minimal agonist activity. Compound 1 was tested in dose escalation studies in rats and dogs and was found to induce cholinergic AEs and convulsion at therapeutic indices similar to previous compounds with more agonist activity. These findings provide preliminary evidence that positive allosteric modulation of M is sufficient to elicit cholinergic AEs.
[Mh] Termos MeSH primário: Isoindóis/farmacologia
Lactamas/farmacologia
Oxazóis/farmacologia
Receptor Muscarínico M1/agonistas
Convulsões/induzido quimicamente
[Mh] Termos MeSH secundário: Regulação Alostérica
Anfetamina/farmacologia
Animais
Ataxia/induzido quimicamente
Diarreia/induzido quimicamente
Cães
Desenho de Drogas
Feminino
Seres Humanos
Indanos/farmacologia
Isoindóis/administração & dosagem
Isoindóis/síntese química
Isoindóis/toxicidade
Lactamas/administração & dosagem
Lactamas/síntese química
Lactamas/toxicidade
Masculino
Camundongos Endogâmicos C57BL
Microssomos Hepáticos/metabolismo
Oxazóis/administração & dosagem
Oxazóis/síntese química
Oxazóis/toxicidade
Piperidinas/farmacologia
Ratos Wistar
Receptor Muscarínico M1/antagonistas & inibidores
Hidrobrometo de Escopolamina/farmacologia
Relação Estrutura-Atividade
Sulfonamidas/farmacologia
Tiadiazóis/farmacologia
Vômito/induzido quimicamente
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Indans); 0 (Isoindoles); 0 (Lactams); 0 (N-(3-oxo-3-(4-(pyridin-4-yl)piperazin-1-yl)propyl)benzo(c)(1,2,5)thiadiazole-4-sulfonamide); 0 (Oxazoles); 0 (PF-06827443); 0 (Piperidines); 0 (Receptor, Muscarinic M1); 0 (Sulfonamides); 0 (Thiadiazoles); 451IFR0GXB (Scopolamine Hydrobromide); 8SSC91326P (donepezil); CK833KGX7E (Amphetamine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170610
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00597


  7 / 1539 MEDLINE  
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[PMID]:28400472
[Au] Autor:Baker JG; Gardiner SM; Woolard J; Fromont C; Jadhav GP; Mistry SN; Thompson KSJ; Kellam B; Hill SJ; Fischer PM
[Ad] Endereço:Cell Signalling Research Group, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom; jillian.baker@nottingham.ac.uk.
[Ti] Título:Novel selective ß -adrenoceptor antagonists for concomitant cardiovascular and respiratory disease.
[So] Source:FASEB J;31(7):3150-3166, 2017 Jul.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:ß-Blockers reduce mortality and improve symptoms in people with heart disease; however, current clinically available ß-blockers have poor selectivity for the cardiac ß -adrenoceptor (AR) over the lung ß -AR. Unwanted ß -blockade risks causing life-threatening bronchospasm and reduced efficacy of ß -agonist emergency rescue therapy. Thus, current life-prolonging ß-blockers are contraindicated in patients with both heart disease and asthma. Here, we describe NDD-713 and -825, novel highly ß -selective neutral antagonists with good pharmaceutical properties that can potentially overcome this limitation. Radioligand binding studies and functional assays that use human receptors expressed in Chinese hamster ovary cells demonstrate that NDD-713 and -825 have nanomolar ß -AR affinity >500-fold ß -AR ß -AR selectivity and no agonism. Studies in conscious rats demonstrate that these antagonists are orally bioavailable and cause pronounced ß -mediated reduction of heart rate while showing no effect on ß -mediated hindquarters vasodilatation. These compounds also have good disposition properties and show no adverse toxicologic effects. They potentially offer a truly cardioselective ß-blocker therapy for the large number of patients with heart and respiratory or peripheral vascular comorbidities.-Baker, J. G., Gardiner, S. M., Woolard, J., Fromont, C., Jadhav, G. P., Mistry, S. N., Thompson, K. S. J., Kellam, B., Hill, S. J., Fischer, P. M. Novel selective ß -adrenoceptor antagonists for concomitant cardiovascular and respiratory disease.
[Mh] Termos MeSH primário: Antagonistas de Receptores Adrenérgicos beta 1/farmacologia
Benzamidas/farmacologia
Isoindóis/farmacologia
[Mh] Termos MeSH secundário: Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem
Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética
Animais
Células CHO
Cricetinae
Cricetulus
Relação Dose-Resposta a Droga
Canal de Potássio ERG1/química
Seres Humanos
Masculino
Testes de Mutagenicidade
Ratos
Ratos Sprague-Dawley
Salmonella typhimurium
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adrenergic beta-1 Receptor Antagonists); 0 (Benzamides); 0 (ERG1 Potassium Channel); 0 (Isoindoles); 0 (KCNH2 protein, human); 0 (NDD-713); 0 (NDD-825)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171117
[Lr] Data última revisão:
171117
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170413
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201601305R


  8 / 1539 MEDLINE  
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[PMID]:28331117
[Au] Autor:Arao T; Okada Y; Torimoto K; Sugai K; Otsuka T; Kurozumi A; Tanaka Y
[Ad] Endereço:Department of Internal Medicine, Japan Labour Health and Safety Organization Kyushu Rosai Hospital, Moji Medical Center, Japan.
[Ti] Título:Comparison Between Effectiveness of 100 mg/day Sitagliptin and a Switch to Mitiglinide Calcium Hydrate/Voglibose from 50 mg/day Sitagliptin in Patients with Type 2 Diabetes.
[So] Source:J UOEH;39(1):1-9, 2017.
[Is] ISSN:0387-821X
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:We analyzed the effects of 100 mg/day sitagliptin and a switch to mitiglinide calcium hydrate/voglibose compound tablets (MIT/VOG) in patients with type 2 diabetes mellitus (T2DM) treated with 50 mg/day sitagliptin. Five patients with T2DM treated with 50 mg/day sitagliptin and hemoglobin A1c (HbA1c) of ≥6.5% were switched to MIT/VOG, or the dose of sitagliptin was increased to 100 mg/day. The effects of the changes in therapy were compared in a crossover fashion by continuous glucose monitoring. The primary endpoint was mean amplitude of glycemic excursions (MAGE), and the secondary end points were 24-hour mean blood glucose level and mean blood glucose level from 0:00 a.m. to 7:00 a.m. and from 7:00 a.m. to 0:00 a.m., percentage of time with blood glucose level of ≥200 mg/dl and <70 mg/dl, maximum and minimum blood glucose levels, and increases in postprandial blood glucose levels. MAGE was significantly lower with MIT/VOG (P = 0.016), whereas mean blood glucose levels were lower between 0:00 a.m. and 7:00 a.m. with 100 mg/day sitagliptin. The percentage of time with blood glucose level ≥200 mg/dl was significantly shorter with MIT/VOG (P = 0.041). The maximum blood glucose level was significantly lower with MIT/VOG (P = 0.043), and the minimum was significantly lower with 100 mg/day sitagliptin (P = 0.043). Blood glucose levels after dinner and mean increases in postprandial blood glucose levels were significantly lower with MIT/VOG (P = 0.090 and P = 0.045 respectively). In patients with T2DM, treatment with MIT/VOG improves MAGE and postprandial hyperglycemia and 100 mg/day sitagliptin lowers early morning glucose levels. This trial was registered with the University Hospital Medical Information Network (UMIN) (No. UMIN R000008274).
[Mh] Termos MeSH primário: Diabetes Mellitus Tipo 2/tratamento farmacológico
Substituição de Medicamentos
Hipoglicemiantes/administração & dosagem
Inositol/análogos & derivados
Isoindóis/administração & dosagem
Fosfato de Sitagliptina/administração & dosagem
[Mh] Termos MeSH secundário: Adulto
Idoso
Biomarcadores/sangue
Glicemia/análise
Estudos Cross-Over
Diabetes Mellitus Tipo 2/sangue
Quimioterapia Combinada
Feminino
Hemoglobina A Glicada/análise
Seres Humanos
Hiperglicemia/prevenção & controle
Inositol/administração & dosagem
Masculino
Meia-Idade
Monitorização Fisiológica
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Blood Glucose); 0 (Glycated Hemoglobin A); 0 (Hypoglycemic Agents); 0 (Isoindoles); 0 (hemoglobin A1c protein, human); 4L6452S749 (Inositol); D86I0XLB13 (mitiglinide); S77P977AG8 (voglibose); TS63EW8X6F (Sitagliptin Phosphate)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE
[do] DOI:10.7888/juoeh.39.1


  9 / 1539 MEDLINE  
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[PMID]:28331092
[Au] Autor:Realegeno S; Puschnik AS; Kumar A; Goldsmith C; Burgado J; Sambhara S; Olson VA; Carroll D; Damon I; Hirata T; Kinoshita T; Carette JE; Satheshkumar PS
[Ad] Endereço:Poxvirus and Rabies Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
[Ti] Título:Monkeypox Virus Host Factor Screen Using Haploid Cells Identifies Essential Role of GARP Complex in Extracellular Virus Formation.
[So] Source:J Virol;91(11), 2017 Jun 01.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:(MPXV) is a human pathogen that is a member of the genus, which includes and (the causative agent of smallpox). Human monkeypox is considered an emerging zoonotic infectious disease. To identify host factors required for MPXV infection, we performed a genome-wide insertional mutagenesis screen in human haploid cells. The screen revealed several candidate genes, including those involved in Golgi trafficking, glycosaminoglycan biosynthesis, and glycosylphosphatidylinositol (GPI)-anchor biosynthesis. We validated the role of a set of vacuolar protein sorting (VPS) genes during infection, VPS51 to VPS54 (VPS51-54), which comprise the Golgi-associated retrograde protein (GARP) complex. The GARP complex is a tethering complex involved in retrograde transport of endosomes to the -Golgi apparatus. Our data demonstrate that VPS52 and VPS54 were dispensable for mature virion (MV) production but were required for extracellular virus (EV) formation. For comparison, a known antiviral compound, ST-246, was used in our experiments, demonstrating that EV titers in VPS52 and VPS54 knockout (KO) cells were comparable to levels exhibited by ST-246-treated wild-type cells. Confocal microscopy was used to examine actin tail formation, one of the viral egress mechanisms for cell-to-cell dissemination, and revealed an absence of actin tails in VPS52KO- or VPS54KO-infected cells. Further evaluation of these cells by electron microscopy demonstrated a decrease in levels of wrapped viruses (WVs) compared to those seen with the wild-type control. Collectively, our data demonstrate the role of GARP complex genes in double-membrane wrapping of MVs necessary for EV formation, implicating the host endosomal trafficking pathway in orthopoxvirus infection. Human monkeypox is an emerging zoonotic infectious disease caused by (MPXV). Of the two MPXV clades, the Congo Basin strain is associated with severe disease, increased mortality, and increased human-to-human transmission relative to the West African strain. Monkeypox is endemic in regions of western and central Africa but was introduced into the United States in 2003 from the importation of infected animals. The threat of MPXV and other orthopoxviruses is increasing due to the absence of routine smallpox vaccination leading to a higher proportion of naive populations. In this study, we have identified and validated candidate genes that are required for MPXV infection, specifically, those associated with the Golgi-associated retrograde protein (GARP) complex. Identifying host targets required for infection that prevents extracellular virus formation such as the GARP complex or the retrograde pathway can provide a potential target for antiviral therapy.
[Mh] Termos MeSH primário: Endossomos/metabolismo
Interações Hospedeiro-Patógeno
Proteínas de Membrana/genética
Vírus da Varíola dos Macacos/fisiologia
Proteínas de Transporte Vesicular/metabolismo
[Mh] Termos MeSH secundário: Actinas/efeitos dos fármacos
Actinas/metabolismo
Animais
Benzamidas/farmacologia
Transporte Biológico
Linhagem Celular
Genoma Humano
Glicosaminoglicanos/biossíntese
Glicosaminoglicanos/genética
Glicosilfosfatidilinositóis/biossíntese
Complexo de Golgi/genética
Complexo de Golgi/metabolismo
Haploidia
Seres Humanos
Isoindóis/farmacologia
Proteínas de Membrana/metabolismo
Monkeypox/virologia
Mutagênese Insercional
Proteínas de Transporte Vesicular/genética
Carga Viral
Replicação Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (Benzamides); 0 (Glycosaminoglycans); 0 (Glycosylphosphatidylinositols); 0 (Isoindoles); 0 (LRRC32 protein, human); 0 (Membrane Proteins); 0 (ST-246); 0 (VPS53 protein, human); 0 (Vesicular Transport Proteins)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171112
[Lr] Data última revisão:
171112
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE


  10 / 1539 MEDLINE  
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[PMID]:28315670
[Au] Autor:Yoon HY; Hong JI
[Ad] Endereço:Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
[Ti] Título:Sulfatase activity assay using an activity-based probe by generation of N-methyl isoindole under reducing conditions.
[So] Source:Anal Biochem;526:33-38, 2017 Jun 01.
[Is] ISSN:1096-0309
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sulfatases catalyze the hydrolysis of sulfate esters that are present in a range of biomolecules. This is an important step in several biological processes such as cellular degradation, hormone regulation, and cell signaling. We have developed a new activity-based sulfatase probe (probe 1) that generates a fluorescent N-methylisoindole upon hydrolysis by sulfatase. Because of the autoxidation of N-methylisoindole, the sulfatase activity was also tested under reducing conditions, containing either glutathione (GSH) or tris(2-carboxyethyl)phosphine (TCEP), exhibiting little change in kinetic parameters compared to non-reducing conditions. Probe 1 displayed reasonable kinetic parameters under both non-reducing and reducing conditions, among which the use of Tris buffer and Tris buffer containing GSH appeared to be appropriate conditions for inhibitor screening. Probe 1 showed stronger intensity upon treatment with sulfatase under neutral conditions than under acidic conditions, but it still has limitations in the selectivity for a specific sulfatase. Nevertheless, the fluorescent signal generated as a result of the release of N-methylisoindole after treatment of probe 1 with sulfatase provides a new assay for measuring sulfatase activity that could be adapted for high throughput screening.
[Mh] Termos MeSH primário: Glutationa/metabolismo
Isoindóis/metabolismo
Fosfinas/metabolismo
Sulfatases/metabolismo
[Mh] Termos MeSH secundário: Fluorescência
Seres Humanos
Concentração de Íons de Hidrogênio
Hidrólise
Cinética
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Isoindoles); 0 (Phosphines); 22OAC2MO2S (tris(2-carboxyethyl)phosphine); EC 3.1.6.- (Sulfatases); GAN16C9B8O (Glutathione)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170508
[Lr] Data última revisão:
170508
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170320
[St] Status:MEDLINE



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