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[PMID]:28222748
[Au] Autor:Wang Q; Li Y; Dong H; Wang L; Peng J; An T; Yang X; Tian Z; Cai X
[Ad] Endereço:Division of Swine Infectious Diseases, National Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, No.678, Haping street, Xiangfang District, Harbin, 150069, China.
[Ti] Título:Identification of host cellular proteins that interact with the M protein of a highly pathogenic porcine reproductive and respiratory syndrome virus vaccine strain.
[So] Source:Virol J;14(1):39, 2017 Feb 22.
[Is] ISSN:1743-422X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) continues to pose one of the greatest threats to the swine industry. M protein is the most conserved and important structural protein of PRRSV. However, information about the host cellular proteins that interact with M protein remains limited. METHODS: Host cellular proteins that interact with the M protein of HP-PRRSV were immunoprecipitated from MARC-145 cells infected with PRRSV HuN4-F112 using the M monoclonal antibody (mAb). The differentially expressed proteins were identified by LC-MS/MS. The screened proteins were used for bioinformatics analysis including Gene Ontology, the interaction network, and the enriched KEGG pathways. Some interested cellular proteins were validated to interact with M protein by CO-IP. RESULTS: The PRRSV HuN4-F112 infection group had 10 bands compared with the control group. The bands included 219 non-redundant cellular proteins that interact with M protein, which were identified by LC-MS/MS with high confidence. The gene ontology and Kyoto encyclopedia of genes and genomes (KEGG) pathway bioinformatic analyses indicated that the identified proteins could be assigned to several different subcellular locations and functional classes. Functional analysis of the interactome profile highlighted cellular pathways associated with protein translation, infectious disease, and signal transduction. Two interested cellular proteins-nuclear factor of activated T cells 45 kDa (NF45) and proliferating cell nuclear antigen (PCNA)-that could interact with M protein were validated by Co-IP and confocal analyses. CONCLUSIONS: The interactome data between PRRSV M protein and cellular proteins were identified and contribute to the understanding of the roles of M protein in the replication and pathogenesis of PRRSV. The interactome of M protein will aid studies of virus/host interactions and provide means to decrease the threat of PRRSV to the swine industry in the future.
[Mh] Termos MeSH primário: Interações Hospedeiro-Patógeno
Vírus da Síndrome Respiratória e Reprodutiva Suína/fisiologia
Mapeamento de Interação de Proteínas
Proteínas da Matriz Viral/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Cromatografia Líquida
Haplorrinos
Imunoprecipitação
Suínos
Espectrometria de Massas em Tandem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (M protein, porcine reproductive and respiratory syndrome virus); 0 (Viral Matrix Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170823
[Lr] Data última revisão:
170823
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170222
[St] Status:MEDLINE
[do] DOI:10.1186/s12985-017-0700-1


  2 / 41598 MEDLINE  
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[PMID]:28416131
[Au] Autor:Paparin JL; Amador A; Badaroux E; Bot S; Caillet C; Convard T; Da Costa D; Dukhan D; Griffe L; Griffon JF; LaColla M; Leroy F; Liuzzi M; Giulia Loi A; McCarville J; Mascia V; Milhau J; Onidi L; Pierra C; Rahali R; Rosinosky E; Sais E; Seifer M; Surleraux D; Standring D; Dousson CB
[Ad] Endereço:Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP50001, 34189 Montpellier Cedex 4, France. Electronic address: jean-laurent.paparin@merck.com.
[Ti] Título:Discovery of benzophosphadiazine drug candidate IDX375: A novel hepatitis C allosteric NS5B RdRp inhibitor.
[So] Source:Bioorg Med Chem Lett;27(11):2634-2640, 2017 Jun 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells, and as a consequence is an attractive target for selective inhibition. This paper describes the discovery of a novel family of HCV NS5B non-nucleoside inhibitors inspired by the bioisosterism between sulfonamide and phosphonamide. Systematic structural optimization in this new series led to the identification of IDX375, a potent non-nucleoside inhibitor that is selective for genotypes 1a and 1b. The structure and binding domain of IDX375 were confirmed by X-ray co-crystalisation study.
[Mh] Termos MeSH primário: Antivirais/química
Hepacivirus/enzimologia
Lactamas/química
Compostos Organofosforados/química
Proteínas não Estruturais Virais/antagonistas & inibidores
[Mh] Termos MeSH secundário: Regulação Alostérica
Animais
Antivirais/síntese química
Antivirais/metabolismo
Antivirais/farmacologia
Sítios de Ligação
Cristalografia por Raios X
Genótipo
Meia-Vida
Haplorrinos
Hepacivirus/genética
Hepacivirus/fisiologia
Humanos
Lactamas/farmacologia
Camundongos
Simulação de Dinâmica Molecular
Compostos Organofosforados/farmacologia
Estrutura Terciária de Proteína
Ratos
Relação Estrutura-Atividade
Sulfonamidas/química
Proteínas não Estruturais Virais/metabolismo
Replicação Viral/efeitos de drogas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (IDX375); 0 (Lactams); 0 (NS-5 protein, hepatitis C virus); 0 (Organophosphorus Compounds); 0 (Sulfonamides); 0 (Viral Nonstructural Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170821
[Lr] Data última revisão:
170821
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170418
[St] Status:MEDLINE


  3 / 41598 MEDLINE  
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[PMID]:28225826
[Au] Autor:Jean A; Tardy F; Allatif O; Grosjean I; Blanquier B; Gerlier D
[Ad] Endereço:Univ Lyon, SFR BioSciences, ENS de Lyon, Inserm US8, CNRS UMS344, UCBL, Lyon, France.
[Ti] Título:Assessing mycoplasma contamination of cell cultures by qPCR using a set of universal primer pairs targeting a 1.5 kb fragment of 16S rRNA genes.
[So] Source:PLoS One;12(2):e0172358, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mycoplasmas (a generic name for Mollicutes) are a predominant bacterial contaminant of cell culture and cell derived products including viruses. This prokaryote class is characterized by very small size and lack of a cell wall. Consequently, mycoplasmas escape ultrafiltration and visualization under routine microscopic examination, hence the ease with which cells in culture can be contaminated, with routinely more than 10% of cell lines being contaminated. Mycoplasma are a formidable threat both in fundamental research by perverting a whole range of cell properties and functions and in the pharmacological use of cells and cell derived products. Although many methods have been developed, there is still a need for a sensitive, universal assay. Here is reported the development and validation of a quantitative polymerase chain reaction (qPCR) based on the amplification of a 1.5 kb fragment covering the 16S rDNA of the Mollicute class by real-time PCR using universal U1 and U8 degenerate primers. The method includes the addition of a DNA loading probe to each sample to monitor DNA extraction and the absence of PCR inhibitors in the extracted DNA, a positive mycoplasma 16S rDNA traceable reference sample to exclude any accidental contamination of an unknown sample with this reference DNA, an analysis procedure based on the examination of the melting curve and the size of the PCR amplicon, followed by quantification of the number of 16S rDNA copies (with a lower limit of 19 copies) when relevant, and, if useful, the identification of the contaminating prokaryote by sequencing. The method was validated on a collection of mycoplasma strains and by testing over 100 samples of unknown contamination status including stocks of viruses requiring biosafety level 2, 3 or 4 containments. When compared to four established methods, the m16S_qPCR technique exhibits the highest sensitivity in detecting mycoplasma contamination.
[Mh] Termos MeSH primário: Contaminação por DNA
Mycoplasma/isolamento & purificação
RNA Ribossômico 16S/genética
[Mh] Termos MeSH secundário: Animais
Técnicas de Cultura de Células
Linhagem Celular
Cricetinae
Primers do DNA/genética
DNA Bacteriano/genética
Haplorrinos
Humanos
Iguanas
Camundongos
Mycoplasma/genética
Sensibilidade e Especificidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA Primers); 0 (DNA, Bacterial); 0 (RNA, Ribosomal, 16S)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170821
[Lr] Data última revisão:
170821
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170222
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0172358


  4 / 41598 MEDLINE  
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[PMID]:28633899
[Au] Autor:Zheng BZ; D'Andrea SV; Hanumegowda U; Knipe JO; Mosure K; Zhuo X; Lemm JA; Liu M; Rigat KL; Wang YK; Fang H; Poronsky C; Cutrone J; Wu DR; Arunachalam PN; Balapragalathan TJ; Arumugam A; Mathur A; Meanwell NA; Gao M; Roberts SB; Kadow JF
[Ad] Endereço:Department of Discovery Chemistry and Molecular Technologies, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States. Electronic address: zhizhenZheng@bms.com.
[Ti] Título:Discovery of BMS-961955, an allosteric inhibitor of the hepatitis C virus NS5B polymerase.
[So] Source:Bioorg Med Chem Lett;27(15):3294-3300, 2017 Aug 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The synthesis, structure-activity relationship (SAR) data, and further optimization of the metabolic stability and pharmacokinetic (PK) properties for a previously disclosed class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors are described. These efforts led to the discovery of BMS-961955 as a viable contingency backup to beclabuvir which was recently approved in Japan for the treatment of HCV as part of a three drug, single pill combination marketed as Ximency .
[Mh] Termos MeSH primário: Antivirais/química
Antivirais/farmacologia
Benzazepinas/química
Benzazepinas/farmacologia
Hepacivirus/efeitos de drogas
Hepatite C/quimioterapia
Proteínas não Estruturais Virais/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Antivirais/farmacocinética
Benzazepinas/farmacocinética
Cães
Haplorrinos
Hepacivirus/enzimologia
Hepacivirus/metabolismo
Hepatite C/virologia
Humanos
RNA Replicase/antagonistas & inibidores
RNA Replicase/metabolismo
Ratos
Proteínas não Estruturais Virais/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (Benzazepines); 0 (NS-5 protein, hepatitis C virus); 0 (Viral Nonstructural Proteins); EC 2.7.7.48 (RNA Replicase)
[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:170621
[St] Status:MEDLINE


  5 / 41598 MEDLINE  
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[PMID]:28554404
[Au] Autor:Kathrins M
[Ad] Endereço:Division of Urology, Brigham and Women's Hospital, Boston, Massachusetts.
[Ti] Título:Original descriptions of the relationship between epididymal function and sperm morphology.
[So] Source:Fertil Steril;108(1):45-46, 2017 Jul.
[Is] ISSN:1556-5653
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Roussel JD, Stallcup OT, Austin CR. Selective phagocytosis of spermatozoa in the epididymis of bulls, rabits, and monkeys. Fertil Steril 1967;18(4):509-16. "Examination of histologic sections of epididymes revealed the presence of many macrophages in the lumen of all regions, and it was often possible to discern parts of engulfed spermatozoa within the macrophages."
[Mh] Termos MeSH primário: Epididimo/citologia
Epididimo/fisiologia
Macrófagos/fisiologia
Fagocitose/fisiologia
Espermatozoides/citologia
Espermatozoides/fisiologia
[Mh] Termos MeSH secundário: Animais
Bovinos
Haplorrinos
Masculino
Coelhos
Especificidade da Espécie
[Pt] Tipo de publicação:EDITORIAL; REVIEW
[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:170530
[St] Status:MEDLINE


  6 / 41598 MEDLINE  
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[PMID]:28193685
[Au] Autor:Schomers MR; Garagnani M; Pulvermüller F
[Ad] Endereço:Brain Language Laboratory, Freie Universität Berlin, 14195 Berlin, Germany, malte2011@cantab.net.
[Ti] Título:Neurocomputational Consequences of Evolutionary Connectivity Changes in Perisylvian Language Cortex.
[So] Source:J Neurosci;37(11):3045-3055, 2017 Mar 15.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The human brain sets itself apart from that of its primate relatives by specific neuroanatomical features, especially the strong linkage of left perisylvian language areas (frontal and temporal cortex) by way of the arcuate fasciculus (AF). AF connectivity has been shown to correlate with verbal working memory-a specifically human trait providing the foundation for language abilities-but a mechanistic explanation of any related causal link between anatomical structure and cognitive function is still missing. Here, we provide a possible explanation and link, by using neurocomputational simulations in neuroanatomically structured models of the perisylvian language cortex. We compare networks mimicking key features of cortical connectivity in monkeys and humans, specifically the presence of relatively stronger higher-order "jumping links" between nonadjacent perisylvian cortical areas in the latter, and demonstrate that the emergence of working memory for syllables and word forms is a functional consequence of this structural evolutionary change. We also show that a mere increase of learning time is not sufficient, but that this specific structural feature, which entails higher connectivity degree of relevant areas and shorter sensorimotor path length, is crucial. These results offer a better understanding of specifically human anatomical features underlying the language faculty and their evolutionary selection advantage. Why do humans have superior language abilities compared to primates? Recently, a uniquely human neuroanatomical feature has been demonstrated in the strength of the arcuate fasciculus (AF), a fiber pathway interlinking the left-hemispheric language areas. Although AF anatomy has been related to linguistic skills, an explanation of how this fiber bundle may support language abilities is still missing. We use neuroanatomically structured computational models to investigate the consequences of evolutionary changes in language area connectivity and demonstrate that the human-specific higher connectivity degree and comparatively shorter sensorimotor path length implicated by the AF entail emergence of verbal working memory, a prerequisite for language learning. These results offer a better understanding of specifically human anatomical features for language and their evolutionary selection advantage.
[Mh] Termos MeSH primário: Evolução Biológica
Córtex Cerebral/fisiologia
Linguagem
Modelos Genéticos
Modelos Neurológicos
Plasticidade Neuronal/genética
[Mh] Termos MeSH secundário: Animais
Aqueduto do Mesencéfalo/fisiologia
Simulação por Computador
Conectoma/métodos
Haplorrinos
Humanos
Macaca
Pan troglodytes
Especificidade da Espécie
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170214
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.2693-16.2017


  7 / 41598 MEDLINE  
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[PMID]:28569831
[Au] Autor:Cyranoski D
[Ti] Título:Trials of embryonic stem cells to launch in China.
[So] Source:Nature;546(7656):15-16, 2017 05 31.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Mh] Termos MeSH primário: Ensaios Clínicos como Assunto/ética
Células-Tronco Embrionárias Humanas/transplante
Degeneração Macular/terapia
Doença de Parkinson/terapia
[Mh] Termos MeSH secundário: Animais
China
Ensaios Clínicos como Assunto/normas
Dopamina/biossíntese
Dopamina/secreção
Rejeição de Enxerto/prevenção & controle
Haplorrinos
Células-Tronco Embrionárias Humanas/citologia
Humanos
Degeneração Macular/cirurgia
Células-Tronco Neurais/citologia
Células-Tronco Neurais/metabolismo
Células-Tronco Neurais/transplante
Doença de Parkinson/cirurgia
[Pt] Tipo de publicação:NEWS
[Nm] Nome de substância:
VTD58H1Z2X (Dopamine)
[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:170601
[St] Status:MEDLINE
[do] DOI:10.1038/546015a


  8 / 41598 MEDLINE  
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[PMID]:28125696
[Au] Autor:Fuentes-Ramírez A; Jiménez-Soto M; Castro R; Romero-Zuñiga JJ; Dolz G
[Ad] Endereço:Maestría en Enfermedades Tropicales, Posgrado Regional en Ciencias Veterinarias Tropicales (PCVET), Universidad Nacional (UNA), Campus Benjamín Nuñez, Barreal de Heredia, Costa Rica.
[Ti] Título:Molecular Detection of Plasmodium malariae/Plasmodium brasilianum in Non-Human Primates in Captivity in Costa Rica.
[So] Source:PLoS One;12(1):e0170704, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:One hundred and fifty-two blood samples of non-human primates of thirteen rescue centers in Costa Rica were analyzed to determine the presence of species of Plasmodium using thick blood smears, semi-nested multiplex polymerase chain reaction (SnM-PCR) for species differentiation, cloning and sequencing for confirmation. Using thick blood smears, two samples were determined to contain the Plasmodium malariae parasite, with SnM-PCR, a total of five (3.3%) samples were positive to P. malariae, cloning and sequencing confirmed both smear samples as P. malariae. One sample amplified a larger and conserved region of 18S rDNA for the genus Plasmodium and sequencing confirmed the results obtained microscopically and through SnM-PCR tests. Sequencing and construction of a phylogenetic tree of this sample revealed that the P. malariae/P. brasilianum parasite (GenBank KU999995) found in a howler monkey (Alouatta palliata) is identical to that recently reported in humans in Costa Rica. The SnM-PCR detected P. malariae/P. brasilianum parasite in different non-human primate species in captivity and in various regions of the southern Atlantic and Pacific coast of Costa Rica. The similarity of the sequences of parasites found in humans and a monkey suggests that monkeys may be acting as reservoirs of P.malariae/P. brasilianum, for which reason it is important, to include them in control and eradication programs.
[Mh] Termos MeSH primário: DNA de Protozoário/genética
Haplorrinos/parasitologia
Malária/veterinária
Doenças dos Macacos/epidemiologia
Plasmodium malariae/isolamento & purificação
Plasmodium/isolamento & purificação
[Mh] Termos MeSH secundário: Animais
Costa Rica/epidemiologia
Reservatórios de Doenças/parasitologia
Monitoramento Epidemiológico
Feminino
Humanos
Malária/diagnóstico
Malária/epidemiologia
Malária/parasitologia
Masculino
Doenças dos Macacos/diagnóstico
Doenças dos Macacos/parasitologia
Filogenia
Plasmodium/classificação
Plasmodium/genética
Plasmodium malariae/classificação
Plasmodium malariae/genética
RNA Ribossômico 18S/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Protozoan); 0 (RNA, Ribosomal, 18S)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170810
[Lr] Data última revisão:
170810
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170126
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0170704


  9 / 41598 MEDLINE  
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[PMID]:28454849
[Au] Autor:Aikawa K; Asano M; Ono K; Habuka N; Yano J; Wilson K; Fujita H; Kandori H; Hara T; Morimoto M; Santou T; Yamaoka M; Nakayama M; Hasuoka A
[Ad] Endereço:Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: katsuji.aikawa@takeda.com.
[Ti] Título:Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs) Part III: Discovery of 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2f as a clinical candidate.
[So] Source:Bioorg Med Chem;25(13):3330-3349, 2017 Jul 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:We previously reported that 4-(pyrrolidin-1-yl)benzonitrile derivative 1b was a selective androgen receptor modulator (SARM) that exhibited anabolic effects on organs such as muscles and the central nervous system (CNS), but neutral effects on the prostate. From further modification, we identified that 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2a showed strong AR binding affinity with improved metabolic stabilities. Based on these results, we tried to enhance the AR agonistic activities by modifying the substituents of the 5-oxopyrrolidine ring. As a consequence, we found that 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (2f) had ideal SARM profiles in Hershberger assay and sexual behavior induction assay. Furthermore, 2f showed good pharmacokinetic profiles in rats, dogs, monkeys, excellent nuclear selectivity and acceptable toxicological profiles. We also determined its binding mode by obtaining the co-crystal structures with AR.
[Mh] Termos MeSH primário: Androgênios/farmacologia
Descoberta de Drogas
Nitrilos/farmacologia
Receptores Androgênicos/metabolismo
[Mh] Termos MeSH secundário: Androgênios/síntese química
Androgênios/química
Animais
Células COS
Cercopithecus aethiops
Cães
Relação Dose-Resposta a Droga
Haplorrinos
Humanos
Masculino
Camundongos
Microssomos Hepáticos/química
Microssomos Hepáticos/metabolismo
Estrutura Molecular
Nitrilos/síntese química
Nitrilos/química
Ratos
Ratos Sprague-Dawley
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androgens); 0 (Nitriles); 0 (Receptors, Androgen); 9V9APP5H5S (benzonitrile)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170803
[Lr] Data última revisão:
170803
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE


  10 / 41598 MEDLINE  
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[PMID]:28621538
[Au] Autor:Lorthiois E; Anderson K; Vulpetti A; Rogel O; Cumin F; Ostermann N; Steinbacher S; Mac Sweeney A; Delgado O; Liao SM; Randl S; Rüdisser S; Dussauge S; Fettis K; Kieffer L; de Erkenez A; Yang L; Hartwieg C; Argikar UA; La Bonte LR; Newton R; Kansara V; Flohr S; Hommel U; Jaffee B; Maibaum J
[Ad] Endereço:Novartis Pharma AG, Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
[Ti] Título:Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo.
[So] Source:J Med Chem;60(13):5717-5735, 2017 Jul 13.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The highly specific S1 serine protease factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic associations in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead 7 has led to the discovery of noncovalent reversible and selective human factor D (FD) inhibitors with drug-like properties. The orally bioavailable compound 2 exerted excellent potency in 50% human whole blood in vitro and blocked AP activity ex vivo after oral administration to monkeys as demonstrated by inhibition of membrane attack complex (MAC) formation. Inhibitor 2 demonstrated sustained oral and ocular efficacy in a model of lipopolysaccharide (LPS)-induced systemic AP activation in mice expressing human FD.
[Mh] Termos MeSH primário: Fator D do Complemento/antagonistas & inibidores
Via Alternativa do Complemento/efeitos de drogas
Prolina/análogos & derivados
Prolina/farmacologia
[Mh] Termos MeSH secundário: Administração Oral
Animais
Síndrome Hemolítico-Urêmica Atípica/quimioterapia
Síndrome Hemolítico-Urêmica Atípica/imunologia
Fator D do Complemento/imunologia
Complexo de Ataque à Membrana do Sistema Complemento/antagonistas & inibidores
Complexo de Ataque à Membrana do Sistema Complemento/imunologia
Feminino
Haplorrinos
Humanos
Macaca fascicularis
Degeneração Macular/quimioterapia
Degeneração Macular/imunologia
Masculino
Camundongos
Prolina/administração & dosagem
Prolina/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement Membrane Attack Complex); 9DLQ4CIU6V (Proline); EC 3.4.21.46 (Complement Factor D)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170616
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00425



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