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[PMID]:29390377
[Au] Autor:Trifan A; Stanciu C; Gheorghe L; Iacob S; Curescu M; Cijevschi Prelipcean C; Stefanescu G; Girleanu I; Chiriac S; Mihai C; Brisc C; Goldis A; Sporea I; Miftode E; Bataga S; Rogoveanu I; Preda C; Caruntu FA; Singeap AM
[Ad] Endereço:"Grigore T. Popa" University of Medicine and Pharmacy Iasi.
[Ti] Título:Efficacy and safety of paritaprevir/ritonavir, ombitasvir, and dasabuvir with ribavirin for the treatment of HCV genotype 1b compensated cirrhosis in patients aged 70 years or older.
[So] Source:Medicine (Baltimore);96(50):e9271, 2017 Dec.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Advanced age has been a major limitation of interferon-based treatment for chronic hepatitis C virus (HCV) infection because of its poor response and tolerability. Direct-acting antiviral (DAA) drug regimens are safe and highly effective, allowing administration of treatment also in elderly. This study aims to assess the efficacy and safety of paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) with ribavirin for the treatment of patients aged ≥70 years with HCV genotype 1b compensated cirrhosis.A total of 1008 patients with HCV genotype 1b compensated cirrhosis were prospectively treated with PrOD + ribavirin for 12 weeks, between December 2015 and July 2016. Sustained virologic response 12 weeks after the end of treatment (SVR12), adverse effects (AEs), comorbidities, discontinuation, and death rates were recorded. Efficacy and safety of therapy were assessed in patients aged ≥70 years and compared with data from patients <70 years.There were 117 patients aged ≥70 years, preponderantly females (58.9%), mean age 73.3 ±â€Š2.8 years (range 70-82), and 37 (31.6%) were treatment-experienced. Comorbidities were reported in 60.6% of patients ≥70 years and in 39.8% of those <70 years (P < .001). SVR12 rates based on intention-to-treat and per-protocol analyses were 97.4% and 100%, respectively, in patients ≥70 years, compared to 97.8% and 99.6%, respectively, in patients <70 years (P = ns and P = ns). Severe AEs were reported in 4 (3.4%) patients ≥70 years, compared to 23 (2.6%) in those <70 years (P = ns). One death was recorded in a patient aged 79 years (0.9%) and 6 deaths (0.8%) in those <70 years (P = ns).Treatment with PrOD + ribavirin in patients 70 years of age or older with HCV genotype 1b compensated cirrhosis proved as effective, safe, and well tolerated, as it did in younger patients.
[Mh] Termos MeSH primário: Antivirais/uso terapêutico
Hepatite C Crônica/tratamento farmacológico
Cirrose Hepática/tratamento farmacológico
Cirrose Hepática/virologia
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Anilidas/uso terapêutico
Carbamatos/uso terapêutico
Farmacorresistência Viral
Quimioterapia Combinada
Feminino
Genótipo
Seres Humanos
Compostos Macrocíclicos/uso terapêutico
Masculino
Estudos Prospectivos
Ribavirina/uso terapêutico
Ritonavir/uso terapêutico
Sulfonamidas/uso terapêutico
Resposta Viral Sustentada
Uracila/análogos & derivados
Uracila/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABT-267); 0 (ABT-333); 0 (ABT-450); 0 (Anilides); 0 (Antiviral Agents); 0 (Carbamates); 0 (Macrocyclic Compounds); 0 (Sulfonamides); 49717AWG6K (Ribavirin); 56HH86ZVCT (Uracil); O3J8G9O825 (Ritonavir)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180301
[Lr] Data última revisão:
180301
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180203
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009271


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[PMID]:29311466
[Au] Autor:Goto Y
[Ad] Endereço:Department of Chemistry, Graduate School of Science, The University of Tokyo.
[Ti] Título:[Elaboration of Pseudo-natural Products Using Artificial In Vitro Biosynthesis Systems].
[So] Source:Yakugaku Zasshi;138(1):55-61, 2018.
[Is] ISSN:1347-5231
[Cp] País de publicação:Japan
[La] Idioma:jpn
[Ab] Resumo:Peptidic natural products often consist of not only proteinogenic building blocks but also unique non-proteinogenic structures such as macrocyclic scaffolds and N-methylated backbones. Since such non-proteinogenic structures are important structural motifs that contribute to diverse bioactivity, we have proposed that peptides with non-proteinogenic structures should be attractive candidates as artificial bioactive peptides mimicking natural products, or so-called pseudo-natural products. We previously devised an engineered translation system for pseudo-natural peptides, referred to as the flexible in vitro translation (FIT) system. This system enabled "one-pot" synthesis of highly diverse pseudo-natural peptide libraries, which can be rapidly screened by mRNA display technology for the discovery of pseudo-natural peptides with diverse bioactivities.
[Mh] Termos MeSH primário: Produtos Biológicos/química
Reatores Biológicos
Biossíntese de Proteínas
[Mh] Termos MeSH secundário: Perfilação da Expressão Gênica
Compostos Macrocíclicos
Biblioteca de Peptídeos
Peptídeos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Biological Products); 0 (Macrocyclic Compounds); 0 (Peptide Library); 0 (Peptides)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180110
[St] Status:MEDLINE
[do] DOI:10.1248/yakushi.17-00186-3


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[PMID]:29324623
[Au] Autor:Hussar DA
[Ad] Endereço:Remington Professor of Pharmacy Philadelphia College of Pharmacy University of the Sciences Philadelphia, Pa.
[Ti] Título:New Drugs 2018, part 1.
[So] Source:Nursing;48(2):36-44, 2018 Feb.
[Is] ISSN:1538-8689
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Aprovação de Drogas
[Mh] Termos MeSH secundário: Anticorpos Monoclonais/uso terapêutico
Anticorpos Neutralizantes/uso terapêutico
Antipirina/análogos & derivados
Antipirina/uso terapêutico
Benzamidas/uso terapêutico
Benzimidazóis/uso terapêutico
Carbamatos/uso terapêutico
Combinação de Medicamentos
Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico
Seres Humanos
Compostos Macrocíclicos/uso terapêutico
Naltrexona/análogos & derivados
Naltrexona/uso terapêutico
Peptídeos Natriuréticos/uso terapêutico
Piridinas/uso terapêutico
Quinoxalinas/uso terapêutico
Sofosbuvir/uso terapêutico
Sulfonamidas/uso terapêutico
Estados Unidos
United States Food and Drug Administration
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABT-493); 0 (Antibodies, Monoclonal); 0 (Antibodies, Neutralizing); 0 (Benzamides); 0 (Benzimidazoles); 0 (Carbamates); 0 (Drug Combinations); 0 (Heterocyclic Compounds, 4 or More Rings); 0 (Macrocyclic Compounds); 0 (Natriuretic Peptides); 0 (Pyridines); 0 (Quinoxalines); 0 (Sulfonamides); 0 (bezlotoxumab); 0 (naldemedine); 0 (pibrentasvir); 0 (voxilaprevir); 5S6W795CQM (Naltrexone); 74RWP7W0J9 (betrixaban); 7IK8Z952OK (plecanatide); KCU0C7RS7Z (velpatasvir); S798V6YJRP (phenylmethylpyrazolone); T3CHA1B51H (Antipyrine); WJ6CA3ZU8B (Sofosbuvir)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:N
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE
[do] DOI:10.1097/01.NURSE.0000529803.83288.e1


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[PMID]:29325476
[Au] Autor:Chamorro-de-Vega E; Gimenez-Manzorro A; Rodriguez-Gonzalez CG; Escudero-Vilaplana V; De Lorenzo-Pinto A; Iglesias-Peinado I; Herranz-Alonso A; Sanjurjo Saez M; GRUviC Study Group
[Ad] Endereço:a Pharmacy Department , Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón , Madrid , Spain.
[Ti] Título:Twelve weeks of ombitasvir/paritaprevir/r and dasabuvir without ribavirin is effective and safe in the treatment of patients with HCV genotype 1b infection and compensated cirrhosis: results from a real-world cohort study.
[So] Source:Expert Opin Drug Saf;17(3):235-241, 2018 Mar.
[Is] ISSN:1744-764X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To explore the effectiveness and safety of ombitasvir/paritaprevir/ritonavir and dasabuvir (OBV/PTV/r+DSV) for 12 weeks without ribavirin in adults with chronic HCV genotype 1b infection and compensated cirrhosis. METHODS: Observational study of a prospective cohort of adult patients with HCV genotype 1b infection and compensated cirrhosis who received 12 weeks of OBV/PTV/r and DSV without ribavirin. Effectiveness was assessed by recording the percentage of patients achieving sustained virological response at week 12 post-treatment (SVR12). Safety outcomes were based on the incidence of adverse events. RESULTS: Seventy-eight patients were included. The SVR12 rate was 96.1% (95%CI 89.2-99.2). Adverse events were recorded in 78.0% of patients. Of these, 97.7% were grade 1/2. One patient discontinued treatment prematurely owing to adverse events. Eighty-six interactions were detected in 43 patients (55.1%). Overall, 81.4% of interactions required close monitoring, alteration of drug dosage, or timing of administration. In 7.0% of cases, the interactions arose from contraindications that required the suspension of the concomitant drug. In 11.6% of cases, medicinal plants or foods were withdrawn. CONCLUSIONS: The simplified regimen of OBV/PTV/r+DSV administered for 12 weeks is effective and safe in patients with chronic HCV genotype 1b infection and compensated cirrhosis. No adverse reactions related to drug-drug interactions were recorded.
[Mh] Termos MeSH primário: Antivirais/administração & dosagem
Hepacivirus/genética
Hepatite C Crônica/tratamento farmacológico
Cirrose Hepática/tratamento farmacológico
[Mh] Termos MeSH secundário: Idoso
Anilidas/administração & dosagem
Anilidas/efeitos adversos
Antivirais/efeitos adversos
Carbamatos/administração & dosagem
Carbamatos/efeitos adversos
Estudos de Coortes
Interações Medicamentosas
Quimioterapia Combinada
Feminino
Genótipo
Hepatite C Crônica/virologia
Seres Humanos
Cirrose Hepática/virologia
Compostos Macrocíclicos/administração & dosagem
Compostos Macrocíclicos/efeitos adversos
Masculino
Meia-Idade
Estudos Prospectivos
Ritonavir/administração & dosagem
Ritonavir/efeitos adversos
Sulfonamidas/administração & dosagem
Sulfonamidas/efeitos adversos
Resultado do Tratamento
Uracila/administração & dosagem
Uracila/efeitos adversos
Uracila/análogos & derivados
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (ABT-267); 0 (ABT-333); 0 (ABT-450); 0 (Anilides); 0 (Antiviral Agents); 0 (Carbamates); 0 (Macrocyclic Compounds); 0 (Sulfonamides); 56HH86ZVCT (Uracil); O3J8G9O825 (Ritonavir)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180113
[St] Status:MEDLINE
[do] DOI:10.1080/14740338.2018.1424829


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[PMID]:28742329
[Au] Autor:Shi B; Deng Y; Zhao P; Li X
[Ad] Endereço:Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School , 2199 Lishui Road West, Shenzhen 518055, China.
[Ti] Título:Selecting a DNA-Encoded Chemical Library against Non-immobilized Proteins Using a "Ligate-Cross-Link-Purify" Strategy.
[So] Source:Bioconjug Chem;28(9):2293-2301, 2017 09 20.
[Is] ISSN:1520-4812
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:DNA-encoded chemical libraries (DELs) have recently emerged and become an important technology platform in biomedical research and drug discovery. DELs containing large numbers of compounds can be prepared and selected against biological targets to discover novel ligands and inhibitors. In practice, DELs are usually selected against purified and immobilized proteins using the typical "bind-wash-elute" protocol; however, selection methods compatible with non-immobilized proteins would be able to greatly expand the target scope of DELs beyond purified proteins to more-complex and biologically relevant targets. Using a novel "ligate-cross-link-purify" strategy, we report here a method capable of selecting DELs against unmodified and non-immobilized protein targets. In addition, this method has shown excellent capability in identifying binders with moderate and weak affinities.
[Mh] Termos MeSH primário: Reagentes para Ligações Cruzadas/química
DNA/química
Descoberta de Drogas/métodos
Proteínas/metabolismo
Bibliotecas de Moléculas Pequenas/química
Bibliotecas de Moléculas Pequenas/farmacologia
[Mh] Termos MeSH secundário: Reagentes para Ligações Cruzadas/isolamento & purificação
DNA/isolamento & purificação
Seres Humanos
Proteínas Imobilizadas/metabolismo
Ligantes
Compostos Macrocíclicos/química
Compostos Macrocíclicos/isolamento & purificação
Compostos Macrocíclicos/farmacologia
Ligação Proteica
Bibliotecas de Moléculas Pequenas/isolamento & purificação
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cross-Linking Reagents); 0 (Immobilized Proteins); 0 (Ligands); 0 (Macrocyclic Compounds); 0 (Proteins); 0 (Small Molecule Libraries); 9007-49-2 (DNA)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171219
[Lr] Data última revisão:
171219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1021/acs.bioconjchem.7b00343


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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]:28873303
[Au] Autor:Liu G; Huang W; Wang J; Liu X; Yang J; Zhang Y; Geng Y; Tan W; Zhang A
[Ad] Endereço:CAS Key Laboratory of Receptor Research, and the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM) , Shanghai 201203, China.
[Ti] Título:Discovery of Novel Macrocyclic Hedgehog Pathway Inhibitors Acting by Suppressing the Gli-Mediated Transcription.
[So] Source:J Med Chem;60(19):8218-8245, 2017 Oct 12.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A systemic medicinal chemistry campaign was conducted based on a literature hit compound 5 bearing the 4,5-dihydro-2H-benzo[b][1,5]oxazocin-6(3H)-one core through cyclization of two side substituents of the bicyclic skeleton combined with N-atom walking or ring walking and the central ring expansion or extraction approaches, leading to several series of structurally unique tricyclic compounds. Among these, compound 29a was identified as the most potent against the Hedgehog (Hh) signaling pathway showing an IC value of 23 nM. Mechanism studies indicated that compound 29a inhibited the Hh signaling pathway by suppressing the expression of the transcriptional factors Gli rather than by interrupting the binding of Gli with DNA. We further observed that 29a was equally potent against both Smo wild type and the two major resistant mutants (Smo D473H and Smo W535L). It potently inhibited the proliferation of medulloblastoma cells and showed significant tumor growth inhibition in the ptch± ;p53-/- medulloblastoma allograft mice model. Though more studies are needed to clarify the precise interaction pattern of 29a with Gli, its promising in vitro and in vivo properties encourage further profiling as a new-generation Hh signaling inhibitor to treat tumors primarily or secondarily resistant to current Smo inhibitors.
[Mh] Termos MeSH primário: Proteínas Hedgehog/antagonistas & inibidores
Compostos Macrocíclicos/síntese química
Compostos Macrocíclicos/farmacologia
Proteína GLI1 em Dedos de Zinco/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
DNA/metabolismo
Seres Humanos
Meduloblastoma/tratamento farmacológico
Camundongos
Camundongos Knockout
Modelos Moleculares
Mutação/genética
Transdução de Sinais/efeitos dos fármacos
Relação Estrutura-Atividade
Proteína Supressora de Tumor p53/genética
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Gli protein, mouse); 0 (Hedgehog Proteins); 0 (Macrocyclic Compounds); 0 (Tumor Suppressor Protein p53); 0 (Zinc Finger Protein GLI1); 9007-49-2 (DNA)
[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:170906
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b01185


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[PMID]:28858522
[Au] Autor:Kitir B; Maolanon AR; Ohm RG; Colaço AR; Fristrup P; Madsen AS; Olsen CA
[Ad] Endereço:Center for Biopharmaceuticals and Department for Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , DK-2100 Copenhagen, Denmark.
[Ti] Título:Chemical Editing of Macrocyclic Natural Products and Kinetic Profiling Reveal Slow, Tight-Binding Histone Deacetylase Inhibitors with Picomolar Affinities.
[So] Source:Biochemistry;56(38):5134-5146, 2017 Sep 26.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Histone deacetylases (HDACs) are validated targets for treatment of certain cancer types and play numerous regulatory roles in biology, ranging from epigenetics to metabolism. Small molecules are highly important as tool compounds for probing these mechanisms as well as for the development of new medicines. Therefore, detailed mechanistic information and precise characterization of the chemical probes used to investigate the effects of HDAC enzymes are vital. We interrogated Nature's arsenal of macrocyclic nonribosomal peptide HDAC inhibitors by chemical synthesis and evaluation of more than 30 natural products and analogues. This furnished surprising trends in binding affinities for the various macrocycles, which were then exploited for the design of highly potent class I and IIb HDAC inhibitors. Furthermore, thorough kinetic investigation revealed unexpected inhibitory mechanisms of important tool compounds as well as the approved drug Istodax (romidepsin). This work provides novel inhibitors with varying potencies, selectivity profiles, and mechanisms of inhibition and, importantly, affords insight into known tool compounds that will improve the interpretation of their effects in biology and medicine.
[Mh] Termos MeSH primário: Produtos Biológicos/química
Inibidores de Histona Desacetilases/química
Inibidores de Histona Desacetilases/farmacologia
Compostos Macrocíclicos/química
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Antineoplásicos/farmacologia
Técnicas de Química Sintética
Relação Dose-Resposta a Droga
Células HeLa
Inibidores de Histona Desacetilases/administração & dosagem
Histona Desacetilases/metabolismo
Seres Humanos
Cinética
Compostos Macrocíclicos/síntese química
Compostos Macrocíclicos/farmacologia
Pró-Fármacos/farmacologia
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Relação Estrutura-Atividade
Zinco/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Biological Products); 0 (Histone Deacetylase Inhibitors); 0 (Macrocyclic Compounds); 0 (Prodrugs); 0 (Recombinant Proteins); EC 3.5.1.98 (Histone Deacetylases); J41CSQ7QDS (Zinc)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00725


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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]:28758878
[Au] Autor:Shahabadi N; Hakimi M; Morovati T; Fatahi N
[Ad] Endereço:a Inorganic Chemistry Department, Faculty of Chemistry , Razi University , Kermanshah , Iran.
[Ti] Título:DNA binding affinity of a macrocyclic copper(II) complex: Spectroscopic and molecular docking studies.
[So] Source:Nucleosides Nucleotides Nucleic Acids;36(8):497-510, 2017 Aug 03.
[Is] ISSN:1532-2335
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The interaction of a novel macrocyclic copper(II) complex, ([CuL(ClO ) ] that L is 1,3,6,10,12,15-hexaazatricyclo[13.3.1.1 ]eicosane) with calf thymus DNA (ct-DNA) was investigated by various physicochemical techniques and molecular docking at simulated physiological conditions (pH = 7.4). The absorption spectra of the Cu(II) complex with ct-DNA showed a marked hyperchroism with 10 nm blue shift. The intrinsic binding constant (K ) was determined as 1.25 × 10 M , which is more in keeping with the groove binding with DNA. Furthermore, competitive fluorimetric studies with Hoechst33258 have shown that Cu(II) complex exhibits the ability to displace the ct-DNA-bound Hoechst33258 indicating that it binds to ct-DNA in strong competition with Hoechst33258 for the groove binding. Also, no change in the relative viscosity of ct-DNA and fluorescence intensity of ct-DNA-MB complex in the present of Cu(II) complex is another evidence to groove binding. The thermodynamic parameters are calculated by van't Hoff equation, which demonstrated that hydrogen bonds and van der Waals interactions played major roles in the binding reaction. The experimental results were in agreement with the results obtained via molecular docking study.
[Mh] Termos MeSH primário: Cobre/química
DNA/metabolismo
Compostos Macrocíclicos/química
Simulação de Acoplamento Molecular
Compostos Organometálicos/química
Compostos Organometálicos/metabolismo
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/química
Antineoplásicos/metabolismo
Sequência de Bases
Bovinos
DNA/química
DNA/genética
Desenho de Drogas
Conformação de Ácido Nucleico
Análise Espectral
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Macrocyclic Compounds); 0 (Organometallic Compounds); 789U1901C5 (Copper); 9007-49-2 (DNA); 91080-16-9 (calf thymus DNA)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE
[do] DOI:10.1080/15257770.2017.1332370



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