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[PMID]:29191554
[Au] Autor:Futamura-Takahashi J; Tanaka T; Sugawara H; Iwashita S; Imajo S; Oyama Y; Muto T
[Ad] Endereço:Asubio Pharma Co., Ltd, 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan. Electronic address: futamura.junko.b6@asubio.co.jp.
[Ti] Título:Structure-based design, synthesis, and binding mode analysis of novel and potent chymase inhibitors.
[So] Source:Bioorg Med Chem Lett;28(2):188-192, 2018 01 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Based on insight from the X-ray crystal structure of human chymase in complex with compound 1, a lactam carbonyl of the diazepane core was exchanged with O-substituted oxyimino group, leading to amidoxime derivatives. This modification resulted in highly potent chymase inhibitors, such as O-phenylamidoxime 5f. X-ray crystal structure analysis indicated that compound 5f induced movement of the Leu99 and Tyr94 side chains at the S2 site, and the increase in inhibitory activity of O-phenyl amidoxime derivatives suggested that the O-phenyl moiety interacted with the Tyr94 residue. Surface plasmon resonance experiments showed that compound 5f had slower association and dissociation kinetics and the calculated residence time of compound 5f to human chymase was extended compared to that of amide compound 1.
[Mh] Termos MeSH primário: Quimases/antagonistas & inibidores
Desenho de Drogas
Oximas/farmacologia
Inibidores de Serino Proteinase/farmacologia
[Mh] Termos MeSH secundário: Sítios de Ligação/efeitos dos fármacos
Quimases/metabolismo
Relação Dose-Resposta a Droga
Seres Humanos
Estrutura Molecular
Oximas/síntese química
Oximas/química
Inibidores de Serino Proteinase/síntese química
Inibidores de Serino Proteinase/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Oximes); 0 (Serine Proteinase Inhibitors); 0 (amidoxime); EC 3.4.21.39 (Chymases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171202
[St] Status:MEDLINE


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[PMID]:27770804
[Au] Autor:Natarajan K; Gottipati KR; Berhane K; Samten B; Pendurthi U; Boggaram V
[Ad] Endereço:Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, 11937 US Highway 271, Tyler, TX, 75708-3154, USA.
[Ti] Título:Proteases and oxidant stress control organic dust induction of inflammatory gene expression in lung epithelial cells.
[So] Source:Respir Res;17(1):137, 2016 10 22.
[Is] ISSN:1465-993X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Persistant inflammatory responses to infectious agents and other components in organic dust underlie lung injury and development of respiratory diseases. Organic dust components responsible for eliciting inflammation and the mechanisms by which they cause lung inflammation are not fully understood. We studied the mechanisms by which protease activities in poultry dust extracts and intracellular oxidant stress induce inflammatory gene expression in A549 and Beas2B lung epithelial cells. METHODS: The effects of dust extracts on inflammatory gene expression were analyzed by quantitative polymerase chain reaction (qPCR), enzyme linked immunosorbent (ELISA) and western blot assays. Oxidant stress was probed by dihydroethidium (DHE) labeling, and immunostaining for 4-hydroxynonenal (4-HNE). Effects on interleukin-8 (IL-8) promoter regulation were determined by transient transfection assay. RESULTS: Dust extracts contained trypsin and elastase activities, and activated protease activated receptor (PAR)-1 and -2. Serine protease inhibitors and PAR-1 or PAR-2 knockdown suppressed inflammatory gene induction. Dust extract induction of IL-8 gene expression was associated with increased DHE-fluorescence and 4-HNE staining, and antioxidants suppressed inflammatory gene induction. Protease inhibitors and antioxidants suppressed protein kinase C and NF-κB activation and induction of IL-8 promoter activity in cells exposed to dust extract. CONCLUSIONS: Our studies demonstrate that proteases and intracellular oxidants control organic dust induction of inflammatory gene expression in lung epithelial cells. Targeting proteases and oxidant stress may serve as novel approaches for the treatment of organic dust induced lung diseases. This is the first report on the involvement of oxidant stress in the induction of inflammatory gene expression by organic dust.
[Mh] Termos MeSH primário: Poeira
Células Epiteliais/efeitos dos fármacos
Mediadores da Inflamação/metabolismo
Pulmão/efeitos dos fármacos
Compostos Orgânicos/toxicidade
Estresse Oxidativo/efeitos dos fármacos
Peptídeo Hidrolases/metabolismo
Pneumonia/induzido quimicamente
[Mh] Termos MeSH secundário: Células A549
Animais
Anti-Inflamatórios/farmacologia
Antioxidantes/farmacologia
Células Epiteliais/enzimologia
Regulação da Expressão Gênica
Abrigo para Animais
Seres Humanos
Exposição por Inalação/efeitos adversos
Interleucina-8/genética
Interleucina-8/metabolismo
Pulmão/enzimologia
Metaloproteinases da Matriz/genética
Metaloproteinases da Matriz/metabolismo
Pneumonia/enzimologia
Pneumonia/genética
Pneumonia/prevenção & controle
Aves Domésticas
Receptor PAR-1/genética
Receptor PAR-1/metabolismo
Receptor PAR-2/genética
Receptor PAR-2/metabolismo
Inibidores de Serino Proteinase/farmacologia
Transdução de Sinais/efeitos dos fármacos
Fatores de Tempo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, U.S. GOV'T, P.H.S.
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents); 0 (Antioxidants); 0 (Dust); 0 (IL8 protein, human); 0 (Inflammation Mediators); 0 (Interleukin-8); 0 (Organic Chemicals); 0 (Receptor, PAR-1); 0 (Receptor, PAR-2); 0 (Serine Proteinase Inhibitors); EC 3.4.- (Peptide Hydrolases); EC 3.4.24.- (Matrix Metalloproteinases)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


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Alves, Carlos Roberto
Côrtes, Luzia Monteiro de Castro
Texto completo
[PMID]:29175018
[Au] Autor:Alves CR; Souza RS; Charret KDS; Côrtes LMC; Sá-Silva MP; Barral-Veloso L; Oliveira LFG; da Silva FS
[Ad] Endereço:Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Biologia Molecular e Doenças Endêmicas, Avenida Brasil, 4365, Manguinhos, Rio de Janeiro, RJ, CEP: 21040-360, Brazil. Electronic address: calves@ioc.fiocruz.br.
[Ti] Título:Understanding serine proteases implications on Leishmania spp lifecycle.
[So] Source:Exp Parasitol;184:67-81, 2018 Jan.
[Is] ISSN:1090-2449
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Serine proteases have significant functions over a broad range of relevant biological processes to the Leishmania spp lifecycle. Data gathered here present an update on the Leishmania spp serine proteases and the status of these enzymes as part of the parasite degradome. The serine protease genes (n = 26 to 28) in Leishmania spp, which encode proteins with a wide range of molecular masses (35 kDa-115 kDa), are described along with their degrees of chromosomal and allelic synteny. Amid 17 putative Leishmania spp serine proteases, only ∼18% were experimentally demonstrated, as: signal peptidases that remove the signal peptide from secretory pre-proteins, maturases of other proteins and with metacaspase-like activity. These enzymes include those of clans SB, SC and SF. Classical inhibitors of serine proteases are used as tools for the characterization and investigation of Leishmania spp. Endogenous serine protease inhibitors, which are ecotin-like, can act modulating host actions. However, crude or synthetic based-natural serine protease inhibitors, such as potato tuber extract, Stichodactyla helianthus protease inhibitor I, fukugetin and epoxy-α-lapachone act on parasitic serine proteases and are promising leishmanicidal agents. The functional interrelationship between serine proteases and other Leishmania spp proteins demonstrate essential functions of these enzymes in parasite physiology and therefore their value as targets for leishmaniasis treatment.
[Mh] Termos MeSH primário: Leishmania/enzimologia
Leishmania/crescimento & desenvolvimento
Estágios do Ciclo de Vida
Serina Proteases/metabolismo
Inibidores de Serino Proteinase/farmacologia
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Leishmania/classificação
Leishmania/genética
Leishmaniose/tratamento farmacológico
Serina Proteases/química
Serina Proteases/classificação
Serina Proteases/genética
Inibidores de Serino Proteinase/química
Inibidores de Serino Proteinase/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Serine Proteinase Inhibitors); EC 3.4.- (Serine Proteases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180205
[Lr] Data última revisão:
180205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE


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[PMID]:28459663
[Au] Autor:Eslami SM; Nikfar S; Ghasemi M; Abdollahi M
[Ad] Endereço:Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.
[Ti] Título:Does Evolocumab, as a PCSK9 Inhibitor, Ameliorate the Lipid Profile in Familial Hypercholesterolemia Patients? A Meta-Analysis of Randomized Controlled Trials.
[So] Source:J Pharm Pharm Sci;20:81-96, 2017.
[Is] ISSN:1482-1826
[Cp] País de publicação:Canada
[La] Idioma:eng
[Ab] Resumo:Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a member of regulatory serine proteases which is mostly expressed in liver. In the physiological condition, LDL-C binds to LDL receptors (LDLRs) and via endocytosis, LDLRs are degraded. PCSK9 binds to the epidermal growth factor-like repeat A (EGFA) domain of extracellular LDLRs, and then physiological recycling of LDLRs from surface of liver is cancelled, resulting in elevation of circulating LDL-C in plasma. To evaluate whether evolucomab, as PCSK9 inhibitor monoclonal antibody, ameliorates lipid profile in familial hypercholesterolemia (FH) patients, this meta-analysis has been conducted. PubMed, Web of Science (ISI) and Scopus databases were searched for studies which had investigated the efficacy of evolucomab. Types of outcome investigated were percentage changes from baseline of the lipid profile. Our meta-analysis shows that evolucomab at the dosage of 420 mg monthly could decrease LDL-C  by 54.71%, TC by 35.08%, VLDL-C by 28.37 %, ratio of TC to HDL-C by 39.14 %, triglycerides by 12.11 %, and increased HDL-C by 6.06% from baseline compared to placebo at the end of study in FH patients. Our findings indicate that evolocumab could be a hopeful agent for challenging patients, such as statin intolerance or patients who fail to attain the target goal of LDL-C despite consumption of maximum doses of statins. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/farmacologia
HDL-Colesterol/antagonistas & inibidores
LDL-Colesterol/antagonistas & inibidores
Hiperlipoproteinemia Tipo II/tratamento farmacológico
Pró-Proteína Convertase 9/antagonistas & inibidores
Inibidores de Serino Proteinase/farmacologia
[Mh] Termos MeSH secundário: Anticorpos Monoclonais/química
HDL-Colesterol/química
HDL-Colesterol/metabolismo
LDL-Colesterol/química
LDL-Colesterol/metabolismo
Relação Dose-Resposta a Droga
Seres Humanos
Hiperlipoproteinemia Tipo II/metabolismo
Modelos Moleculares
Pró-Proteína Convertase 9/metabolismo
Ensaios Clínicos Controlados Aleatórios como Assunto
Inibidores de Serino Proteinase/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Cholesterol, HDL); 0 (Cholesterol, LDL); 0 (Serine Proteinase Inhibitors); EC 3.4.21.- (PCSK9 protein, human); EC 3.4.21.- (Proprotein Convertase 9); LKC0U3A8NJ (evolocumab)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171222
[Lr] Data última revisão:
171222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.18433/J36C8N


  5 / 6432 MEDLINE  
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[PMID]:28460818
[Au] Autor:Wurtz NR; Parkhurst BL; DeLucca I; Glunz PW; Jiang W; Zhang X; Cheney DL; Bozarth JM; Rendina AR; Wei A; Harper T; Luettgen JM; Wu Y; Wong PC; Seiffert DA; Wexler RR; Priestley ES
[Ad] Endereço:Bristol-Myers Squibb Research and Development, Princeton, NJ 08534, United States. Electronic address: nicholas.wurtz@bms.com.
[Ti] Título:Neutral macrocyclic factor VIIa inhibitors.
[So] Source:Bioorg Med Chem Lett;27(12):2650-2654, 2017 06 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Factor VIIa (FVIIa) inhibitors have shown strong antithrombotic efficacy in preclinical thrombosis models with limited bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful due to the requirement of a basic P1 group to interact with Asp189 in the S1 binding pocket, limiting their membrane permeability. We have combined recently reported neutral P1 binding substituents with a highly optimized macrocyclic chemotype to produce FVIIa inhibitors with low nanomolar potency and enhanced permeability.
[Mh] Termos MeSH primário: Fator VIIa/antagonistas & inibidores
Compostos Macrocíclicos/farmacologia
Inibidores de Serino Proteinase/farmacologia
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Seres Humanos
Compostos Macrocíclicos/síntese química
Compostos Macrocíclicos/química
Estrutura Molecular
Inibidores de Serino Proteinase/síntese química
Inibidores de Serino Proteinase/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Macrocyclic Compounds); 0 (Serine Proteinase Inhibitors); EC 3.4.21.21 (Factor VIIa)
[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:170503
[St] Status:MEDLINE


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[PMID]:29073215
[Au] Autor:Soto AS; Fenoy IM; Sanchez VR; March F; Perrone Sibilia MD; Aldirico MLA; Picchio MS; Arcon N; Acosta PL; Polack FP; Martin V; Goldman A
[Ad] Endereço:Laboratorio de Inmunología, Vacunas y Alergia, CESyMA, Escuela de Ciencia y Tecnología, Universidad Nacional de San Martín, Buenos Aires, Argentina.
[Ti] Título:Toxoplasma gondii serine-protease inhibitor-1: A new adjuvant candidate for asthma therapy.
[So] Source:PLoS One;12(10):e0187002, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Serine-proteases are important players in the pathogenesis of asthma, promoting inflammation and tissue remodeling. It's also known that many serine protease inhibitors display immunomodulatory properties. TgPI-1 is a Toxoplasma gondii protein that exhibits broad spectrum inhibitory activity against serine proteases. In view of the increased prevalence of atopic disorders and the need to develop new treatment strategies we sought to investigate the potential of TgPI-1 for treating respiratory allergies. For this purpose, we developed a therapeutic experimental model. BALB/c mice were rendered allergic by intraperitoneal ovalbumin-alum sensitization and airway-challenged. Once the asthmatic phenotype was achieved, mice were intranasally treated with rTgPI-1 alone or with a mixture of rTgPI-1 and ovalbumin (OVA). A week later mice were given a secondary aerosol challenge. Treatment with rTgPI-1 alone or co-administered with OVA diminished bronchoalveolar eosinophilia, mucus production and peribronchial lung infiltration. This effect was accompanied by a lung resistance reduction of 26.3% and 50.3% respectively. Both treatments resulted in the production of lower levels of IL-4, IL-5, IFN-γ and regulatory IL-10 by thoracic lymph node cells stimulated with OVA. Interestingly, significant decreases in OVA specific IgE and T cell proliferation, and increases in FoxP3+ T cells at local and systemic levels were only detected when the inhibitor was administered along with OVA. These results show that both rTgPI-1 treatments reduced asthma hallmarks. However, co-administration of the inhibitor with the allergen was more effective. Hence, rTgPI-1 emerges as a novel adjuvant candidate for asthma treatment.
[Mh] Termos MeSH primário: Asma/tratamento farmacológico
Inibidores de Serino Proteinase/farmacologia
Toxoplasma
[Mh] Termos MeSH secundário: Alérgenos/imunologia
Animais
Anticorpos Antiprotozoários/sangue
Anticorpos Antiprotozoários/imunologia
Especificidade de Anticorpos
Asma/sangue
Asma/imunologia
Proliferação Celular/efeitos dos fármacos
Citocinas/biossíntese
Interações Medicamentosas
Fatores de Transcrição Forkhead/metabolismo
Camundongos
Camundongos Endogâmicos BALB C
Ovalbumina/uso terapêutico
Proteínas Recombinantes/farmacologia
Proteínas Recombinantes/uso terapêutico
Inibidores de Serino Proteinase/uso terapêutico
Linfócitos T Reguladores/citologia
Linfócitos T Reguladores/efeitos dos fármacos
Linfócitos T Reguladores/imunologia
Linfócitos T Reguladores/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Allergens); 0 (Antibodies, Protozoan); 0 (Cytokines); 0 (Forkhead Transcription Factors); 0 (Foxp3 protein, mouse); 0 (Recombinant Proteins); 0 (Serine Proteinase Inhibitors); 9006-59-1 (Ovalbumin)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171027
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0187002


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[PMID]:28966272
[Au] Autor:Masuda Y; Yamaotsu N; Hirono S
[Ad] Endereço:School of Pharmaceutical Sciences, Kitasato University.
[Ti] Título:Gibbs Free Energy of Hydrolytic Water Molecule in Acyl-Enzyme Intermediates of a Serine Protease: A Potential Application for Computer-Aided Discovery of Mechanism-Based Reversible Covalent Inhibitors.
[So] Source:Chem Pharm Bull (Tokyo);65(10):889-892, 2017.
[Is] ISSN:1347-5223
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:In order to predict the potencies of mechanism-based reversible covalent inhibitors, the relationships between calculated Gibbs free energy of hydrolytic water molecule in acyl-trypsin intermediates and experimentally measured catalytic rate constants (k ) were investigated. After obtaining representative solution structures by molecular dynamics (MD) simulations, hydration thermodynamics analyses using WaterMap™ were conducted. Consequently, we found for the first time that when Gibbs free energy of the hydrolytic water molecule was lower, logarithms of k were also lower. The hydrolytic water molecule with favorable Gibbs free energy may hydrolyze acylated serine slowly. Gibbs free energy of hydrolytic water molecule might be a useful descriptor for computer-aided discovery of mechanism-based reversible covalent inhibitors of hydrolytic enzymes.
[Mh] Termos MeSH primário: Serina Proteases/metabolismo
Inibidores de Serino Proteinase/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
Gabexato/química
Gabexato/metabolismo
Guanidinas/química
Guanidinas/metabolismo
Hidrólise
Simulação de Dinâmica Molecular
Serina Proteases/química
Inibidores de Serino Proteinase/química
Termodinâmica
Água/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Guanidines); 0 (Serine Proteinase Inhibitors); 059QF0KO0R (Water); 4V7M9137X9 (Gabexate); EC 3.4.- (Serine Proteases); Y25LQ0H97D (nafamostat)
[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:171003
[St] Status:MEDLINE
[do] DOI:10.1248/cpb.c17-00425


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[PMID]:28919772
[Au] Autor:Catapano AL; Pirillo A; Norata GD
[Ad] Endereço:Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano.
[Ti] Título:Anti-PCSK9 antibodies for the treatment of heterozygous familial hypercholesterolemia: patient selection and perspectives.
[So] Source:Vasc Health Risk Manag;13:343-351, 2017.
[Is] ISSN:1178-2048
[Cp] País de publicação:New Zealand
[La] Idioma:eng
[Ab] Resumo:Heterozygous familial hypercholesterolemia (FH) is a genetic disorder characterized by high low-density lipoprotein cholesterol levels from birth, which exposes the arteries to high levels of atherogenic lipoproteins lifelong and results in a significantly increased risk of premature cardiovascular events. The diagnosis of FH, followed by an appropriate and early treatment is critical to reduce the cardiovascular burden in this population. Phase I-III clinical trials showed the benefit of proprotein convertase subtilisin kexin 9 inhibitors, both alirocumab and evolocumab, in these patients with an average low-density lipoprotein cholesterol reduction ranging from -40% to -60%. The aim of this review is to address the unmet needs in cholesterol management, elucidate the biology and the clinical benefit of proprotein convertase subtilisin kexin 9 inhibition and finally discuss the open gaps and future directions in the treatment of patients with heterozygous FH.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/uso terapêutico
Anticolesterolemiantes/uso terapêutico
LDL-Colesterol/sangue
Heterozigoto
Hiperlipoproteinemia Tipo II/tratamento farmacológico
Pró-Proteína Convertase 9/antagonistas & inibidores
Inibidores de Serino Proteinase/uso terapêutico
[Mh] Termos MeSH secundário: Adulto
Animais
Anticorpos Monoclonais/efeitos adversos
Anticolesterolemiantes/efeitos adversos
Biomarcadores/sangue
Ensaios Clínicos como Assunto
Medicina Baseada em Evidências
Feminino
Predisposição Genética para Doença
Seres Humanos
Hiperlipoproteinemia Tipo II/sangue
Hiperlipoproteinemia Tipo II/enzimologia
Hiperlipoproteinemia Tipo II/genética
Masculino
Fenótipo
Pró-Proteína Convertase 9/imunologia
Pró-Proteína Convertase 9/metabolismo
Inibidores de Serino Proteinase/efeitos adversos
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Anticholesteremic Agents); 0 (Biomarkers); 0 (Cholesterol, LDL); 0 (Serine Proteinase Inhibitors); EC 3.4.21.- (PCSK9 protein, human); EC 3.4.21.- (Proprotein Convertase 9); LKC0U3A8NJ (evolocumab); PP0SHH6V16 (alirocumab)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170919
[St] Status:MEDLINE
[do] DOI:10.2147/VHRM.S130338


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[PMID]:28780160
[Au] Autor:Wang C; Corte JR; Rossi KA; Bozarth JM; Wu Y; Sheriff S; Myers JE; Luettgen JM; Seiffert DA; Wexler RR; Quan ML
[Ad] Endereço:Bristol-Myers Squibb Company, Research and Development, 350 Carter Road, Hopewell, NJ 08540 United States.
[Ti] Título:Macrocyclic factor XIa inhibitors.
[So] Source:Bioorg Med Chem Lett;27(17):4056-4060, 2017 09 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A series of macrocyclic factor XIa (FXIa) inhibitors was designed based on an analysis of the crystal structures of the acyclic phenylimidazole compounds. Further optimization using structure-based design led to inhibitors with pM affinity for FXIa, excellent selectivity against a panel of relevant serine proteases, and good potency in the activated partial thromboplastin time (aPTT) clotting assay.
[Mh] Termos MeSH primário: Fator XIa/antagonistas & inibidores
Imidazóis/farmacologia
Compostos Macrocíclicos/farmacologia
Inibidores de Serino Proteinase/farmacologia
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Fator XIa/metabolismo
Seres Humanos
Imidazóis/síntese química
Imidazóis/química
Compostos Macrocíclicos/síntese química
Compostos Macrocíclicos/química
Estrutura Molecular
Inibidores de Serino Proteinase/síntese química
Inibidores de Serino Proteinase/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Imidazoles); 0 (Macrocyclic Compounds); 0 (Serine Proteinase Inhibitors); 7GBN705NH1 (imidazole); EC 3.4.21.27 (Factor XIa)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170807
[St] Status:MEDLINE


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[PMID]:28729054
[Au] Autor:Portela AC; Barros TG; Lima CHDS; Dias LRS; Azevedo PHRA; Dantas ASCL; Mohana-Borges R; Ventura GT; Pinheiro S; Muri EMF
[Ad] Endereço:Laboratório de Química Medicinal, Departamento de Tecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Fluminense, Rua Mario Viana 523, Santa Rosa, 24241-000, Niterói, RJ, Brazil.
[Ti] Título:Isosorbide-based peptidomimetics as inhibitors of hepatitis C virus serine protease.
[So] Source:Bioorg Med Chem Lett;27(16):3661-3665, 2017 08 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Hepatitis C infection is a cause of chronic liver diseases such as cirrhosis and carcinoma. The current therapy for hepatitis C has limited efficacy and low tolerance. The HCV encodes a serine protease which is critical for viral replication, and few protease inhibitors are currently on the market. In this paper, we describe the synthesis and screening of novel isosorbide-based peptidomimetic inhibitors, in which the compounds 1d, 1e, and 1i showed significant inhibition of the protease activity in vitro at 100µM. The compound 1e also showed dose-response (IC =36±3µM) and inhibited the protease mutants D168A and V170A at 100µM, indicating it as a promising inhibitor of the HCV NS3/4A protease. Our molecular modeling studies suggest that the activity of 1e is associated with a change in the interactions of S2 and S4 subsites, since that the increased flexibility favors a decrease in activity against D168A, whereas the appearance of a hydrophobic cavity in the S4 subsite increase the inhibition against V170A strain.
[Mh] Termos MeSH primário: Antivirais/química
Hepacivirus/enzimologia
Isossorbida/química
Serina Proteases/química
Inibidores de Serino Proteinase/química
[Mh] Termos MeSH secundário: Antivirais/síntese química
Antivirais/farmacologia
Sítios de Ligação
Domínio Catalítico
Hepacivirus/efeitos dos fármacos
Isossorbida/síntese química
Isossorbida/farmacologia
Simulação de Acoplamento Molecular
Mutação
Peptidomiméticos
Serina Proteases/genética
Serina Proteases/metabolismo
Inibidores de Serino Proteinase/síntese química
Inibidores de Serino Proteinase/farmacologia
Termodinâmica
Proteínas não Estruturais Virais/antagonistas & inibidores
Proteínas não Estruturais Virais/genética
Proteínas não Estruturais Virais/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (NS3 protein, hepatitis C virus); 0 (NS4 protein, hepatitis C virus); 0 (Peptidomimetics); 0 (Serine Proteinase Inhibitors); 0 (Viral Nonstructural Proteins); EC 3.4.- (Serine Proteases); WXR179L51S (Isosorbide)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170722
[St] Status:MEDLINE



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