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[PMID]:28807575
[Au] Autor:Paudel S; Min X; Acharya S; Khadka DB; Yoon G; Kim KM; Cheon SH
[Ad] Endereço:College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea.
[Ti] Título:Triple reuptake inhibitors: Design, synthesis and structure-activity relationship of benzylpiperidine-tetrazoles.
[So] Source:Bioorg Med Chem;25(20):5278-5289, 2017 Oct 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Monoamine transporters are important targets in the treatment of various central nervous disorders. Several limitations of traditional reuptake inhibitors, like delayed onset of action, insomnia, and sexual dysfunction, have compelled the search for safer, more effective compounds. In this study, we have sought to identify novel monoamine reuptake inhibitors. Based upon the docking study of compounds that we had reported previously, aromatic rings (A1) were modified to generate a novel series of benzylpiperidine-tetrazoles. Thirty-one compounds were synthesized and evaluated for their triple reuptake inhibition of serotonin, norepinephrine and dopamine. Triple reuptake inhibitor, compound 2q, in particular, showed potent serotonin reuptake inhibition, validating our design approach.
[Mh] Termos MeSH primário: Desenho de Drogas
Inibidores da Captação de Neurotransmissores/farmacologia
Piperidinas/farmacologia
Tetrazóis/farmacologia
[Mh] Termos MeSH secundário: Dopamina/metabolismo
Relação Dose-Resposta a Droga
Seres Humanos
Simulação de Acoplamento Molecular
Estrutura Molecular
Inibidores da Captação de Neurotransmissores/síntese química
Inibidores da Captação de Neurotransmissores/química
Norepinefrina/antagonistas & inibidores
Norepinefrina/metabolismo
Piperidinas/síntese química
Piperidinas/química
Serotonina/metabolismo
Relação Estrutura-Atividade
Tetrazóis/síntese química
Tetrazóis/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neurotransmitter Uptake Inhibitors); 0 (Piperidines); 0 (Tetrazoles); 333DO1RDJY (Serotonin); 7HZE16210B (1-benzylpiperidine); VTD58H1Z2X (Dopamine); X4W3ENH1CV (Norepinephrine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170816
[St] Status:MEDLINE


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[PMID]:28315869
[Au] Autor:Tang P; Duan C; Wang Z; Wang C; Meng G; Lin K; Yang Q; Yuan Z
[Ad] Endereço:Department of Trauma and Orthopaedics, Xijing Hospital, the Fourth Military Medical University, Xi'an, China.
[Ti] Título:NPY and CGRP Inhibitor Influence on ERK Pathway and Macrophage Aggregation during Fracture Healing.
[So] Source:Cell Physiol Biochem;41(4):1457-1467, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:AIM: The aims of this study are to investigate the effects of neurotransmitters NPY and CGRP on ERK signaling in fracture healing, and to identify the correlation between macrophage aggregation and fracture healing. METHODS: Male Sprague-Dawley rats were used to build a fracture model. The neurotransmitter receptor inhibitors were injected intraperitoneally into the rats. Immunofluorescence staining and ELISA were employed to determine the expression of NPY and CGRP in fracture area and the peripheral blood, respectively. Micro-CT together with histological staining were utilized to assess the fracture healing conditions. Relative protein expression was determined using western blot. Immunofluorescence staining was used to detect the aggregation of macrophages in the injury area. RESULTS: During fracture healing, the serum NPY and CGRP significantly increased. The levels of NPY and CGRP reached a peak in the 8th week and reduced significantly thereafter. NPY and CGRP inhibitors could inhibit fracture healing and down-regulate the phosphorylated ERK. Macrophages (NPY+ and CGRP+) aggregated in the injury area. CONCLUSION: NPY and CGRP participated in fracture healing, in which they were also shown to influence phosphorylated ERK expression. In addition, macrophages are involved in the fracture healing process.
[Mh] Termos MeSH primário: Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores
Consolidação da Fratura/efeitos dos fármacos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Macrófagos/metabolismo
Neuropeptídeo Y/antagonistas & inibidores
Inibidores da Captação de Neurotransmissores/farmacologia
[Mh] Termos MeSH secundário: Animais
Macrófagos/patologia
Masculino
Ratos
Ratos Sprague-Dawley
Microtomografia por Raio-X
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neuropeptide Y); 0 (Neurotransmitter Uptake Inhibitors); 83652-28-2 (Calcitonin Gene-Related Peptide)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170621
[Lr] Data última revisão:
170621
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170320
[St] Status:MEDLINE
[do] DOI:10.1159/000468405


  3 / 1155 MEDLINE  
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[PMID]:28274674
[Au] Autor:Paudel S; Acharya S; Yoon G; Kim KM; Cheon SH
[Ad] Endereço:College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea.
[Ti] Título:Design, synthesis and in vitro activity of 1,4-disubstituted piperazines and piperidines as triple reuptake inhibitors.
[So] Source:Bioorg Med Chem;25(7):2266-2276, 2017 Apr 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Monoamine transporters regulate the concentration of monoamine neurotransmitters, which are essential for vital physiological processes, and their dysfunction can cause several central nervous system diseases. Monoamine transporters currently appear to be the potential target in the management of these disorders. In this study, homologation and bioisosterism techniques have been used in the designing of new 1,4-disubstituted piperazines and piperidines. These derivatives were synthesized and evaluated as potential triple reuptake inhibitors for studying the structure-activity relationships. The most advanced compound, 1-(4-(5-benzhydryl-1H-tetrazol-1-yl)butyl)-4-(3-phenylpropyl)piperazine (2i), was able to inhibit monoamine neurotransmitter reuptake in an in vitro test (IC =158.7nM for 5-HT, 99nM for NE and 97.5nM for DA). These novel potent triple reuptake inhibitor-based 1,4-disubstituted piperazine and piperidine scaffolds deserve further systematic optimization and pharmacological evaluation.
[Mh] Termos MeSH primário: Inibidores da Captação de Neurotransmissores/química
Inibidores da Captação de Neurotransmissores/farmacologia
Piperazinas/química
Piperazinas/farmacologia
Piperidinas/química
Piperidinas/farmacologia
[Mh] Termos MeSH secundário: Células HEK293
Seres Humanos
Técnicas In Vitro
Inibidores da Captação de Neurotransmissores/síntese química
Piperazinas/síntese química
Piperidinas/síntese química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neurotransmitter Uptake Inhibitors); 0 (Piperazines); 0 (Piperidines)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170310
[St] Status:MEDLINE


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[PMID]:27650729
[Au] Autor:Shimshoni JA; Winkler I; Golan E; Nutt D
[Ad] Endereço:Department of Toxicology, Kimron Veterinary Institute, Bet Dagan, Israel. jakobs@moag.gov.il.
[Ti] Título:Neurochemical binding profiles of novel indole and benzofuran MDMA analogues.
[So] Source:Naunyn Schmiedebergs Arch Pharmacol;390(1):15-24, 2017 Jan.
[Is] ISSN:1432-1912
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:3,4-Methylenedioxy-N-methylamphetamine (MDMA) has been shown to be effective in the treatment of post-traumatic stress disorder (PTSD) in numerous clinical trials. In the present study, we have characterized the neurochemical binding profiles of three MDMA-benzofuran analogues (1-(benzofuran-5-yl)-propan-2-amine, 5-APB; 1-(benzofuran-6-yl)-N-methylpropan-2-amine, 6-MAPB; 1-(benzofuran-5-yl)-N-methylpropan-2-amine, 5-MAPB) and one MDMA-indole analogue (1-(1H-indol-5-yl)-2-methylamino-propan-1-ol, 5-IT). These compounds were screened as potential second-generation anti-PTSD drugs, against a battery of human and non-human receptors, transporters, and enzymes, and their potencies as 5-HT receptor agonist and monoamine uptake inhibitors determined. All MDMA analogues displayed high binding affinities for 5-HT and NE receptors, as well as significant 5-HT, DA, and NE uptake inhibition. 5-APB revealed significant agonist activity at the 5-HT receptors, while 6-MAPB, 5-MAPB, and 5-IT exhibited significant agonist activity at the 5-HT receptor. There was a lack of correlation between the results of functional uptake and the monoamine transporter binding assay. MDMA analogues emerged as potent and selective monoamine oxidase A inhibitors. Based on 6-MAPB favorable pharmacological profile, it was further subjected to IC determination for monoamine transporters. Overall, all MDMA analogues displayed higher monoamine receptor/transporter binding affinities and agonist activity at the 5-HT receptors as compared to MDMA.
[Mh] Termos MeSH primário: Benzofuranos/metabolismo
Indóis/metabolismo
N-Metil-3,4-Metilenodioxianfetamina/metabolismo
Inibidores da Captação de Neurotransmissores/metabolismo
Receptores 5-HT2 de Serotonina/metabolismo
Agonistas de Receptores 5-HT2 de Serotonina/metabolismo
Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico
Proteínas Vesiculares de Transporte de Monoamina/metabolismo
[Mh] Termos MeSH secundário: Benzofuranos/química
Benzofuranos/farmacologia
Sítios de Ligação
Catecol O-Metiltransferase/química
Catecol O-Metiltransferase/metabolismo
Seres Humanos
Indóis/química
Indóis/farmacologia
Monoaminoxidase/química
Monoaminoxidase/metabolismo
Inibidores da Monoaminoxidase/química
Inibidores da Monoaminoxidase/metabolismo
Inibidores da Monoaminoxidase/farmacologia
N-Metil-3,4-Metilenodioxianfetamina/química
N-Metil-3,4-Metilenodioxianfetamina/farmacologia
Inibidores da Captação de Neurotransmissores/química
Inibidores da Captação de Neurotransmissores/farmacologia
Ligação Proteica
Conformação Proteica
Ensaio Radioligante
Receptores 5-HT2 de Serotonina/química
Receptores 5-HT2 de Serotonina/efeitos dos fármacos
Agonistas de Receptores 5-HT2 de Serotonina/química
Agonistas de Receptores 5-HT2 de Serotonina/farmacologia
Transtornos de Estresse Pós-Traumáticos/metabolismo
Relação Estrutura-Atividade
Tirosina 3-Mono-Oxigenase/química
Tirosina 3-Mono-Oxigenase/metabolismo
Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores
Proteínas Vesiculares de Transporte de Monoamina/química
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzofurans); 0 (Indoles); 0 (Monoamine Oxidase Inhibitors); 0 (Neurotransmitter Uptake Inhibitors); 0 (Receptors, Serotonin, 5-HT2); 0 (Serotonin 5-HT2 Receptor Agonists); 0 (Vesicular Monoamine Transport Proteins); EC 1.14.16.2 (Tyrosine 3-Monooxygenase); EC 1.4.3.4 (Monoamine Oxidase); EC 2.1.1.6 (Catechol O-Methyltransferase); KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160922
[St] Status:MEDLINE
[do] DOI:10.1007/s00210-016-1297-4


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[PMID]:27754966
[Au] Autor:Kapellen TM; Reimann R; Kiess W; Kostev K
[Ti] Título:Prevalence of medically treated children with ADHD and type 1 diabetes in Germany - Analysis of two representative databases.
[So] Source:J Pediatr Endocrinol Metab;29(11):1293-1297, 2016 Nov 01.
[Is] ISSN:2191-0251
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The aim of this study was to analyze the prevalence of attention deficit hyperactivity disorder (ADHD) in children and adolescents with type 1 diabetes mellitus (T1DM) in Germany. METHODS: Two different representative German databases - IMS®-Disease Analyzer, a database that includes diagnoses as well as other information, and IMS®-LRx, a database that documents prescriptions - were used to conduct a retrospective analysis. We searched the LRx database for patients who received both insulin and ADHD-specific medication. RESULTS: In 2014, 677,587 children and adolescents aged 0-18 years were treated by a pediatrician and documented in the Disease Analyzer database. Of these patients, 16,833 received the International Statistical Classification of Diseases and Related Health Problems (ICD-10) diagnosis of ADHD (2.5%) and 3668 patients were treated for T1DM (0.1%). Of these 3668 patients, a total of 153 children were also diagnosed with ADHD (4.2%; p<0.05). In the LRx database, the overall prevalence of children in Germany who received both drugs for the treatment of ADHD and insulin in 2014 amounted to 2.9%. Diagnosis of ADHD is 2.4-3.3 times more frequent in boys than in girls. The highest prevalence was seen in the age group of 12-15 years (3.5%) and the lowest in the age group of 6-11 years (2.5%). CONCLUSIONS: Children with diabetes suffer from ADHD significantly more frequently than children without diabetes. The prevalence of medically treated children with ADHD and diabetes is similar to that documented in a recent report by the Barmer GEK health insurance body. However, it is possible that children with T1DM are much more frequently seen by medical care providers and are thus more likely to be evaluated and receive an appropriate diagnosis.
[Mh] Termos MeSH primário: Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico
Diabetes Mellitus Tipo 1/tratamento farmacológico
Hipoglicemiantes/uso terapêutico
Insulina/uso terapêutico
Inibidores da Captação de Neurotransmissores/uso terapêutico
[Mh] Termos MeSH secundário: Adolescente
Fatores Etários
Cloridrato de Atomoxetina/uso terapêutico
Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia
Criança
Estudos de Coortes
Comorbidade
Dextroanfetamina/uso terapêutico
Diabetes Mellitus Tipo 1/epidemiologia
Prescrições de Medicamentos
Feminino
Alemanha/epidemiologia
Seres Humanos
Masculino
Metilfenidato/uso terapêutico
Prevalência
Estudos Prospectivos
Fatores de Risco
Fatores Sexuais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hypoglycemic Agents); 0 (Insulin); 0 (Neurotransmitter Uptake Inhibitors); 207ZZ9QZ49 (Methylphenidate); 57WVB6I2W0 (Atomoxetine Hydrochloride); TZ47U051FI (Dextroamphetamine)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170503
[Lr] Data última revisão:
170503
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161105
[St] Status:MEDLINE


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[PMID]:27516199
[Au] Autor:Morigi R; Rambaldi M; Locatelli A; Leoni A
[Ti] Título:Small-Molecules Targeting Kinases Involved in Pulmonary Hypertension: a Patent Review (2010-2015).
[So] Source:Curr Med Chem;23(30):3510-3527, 2016.
[Is] ISSN:1875-533X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Despite the fact that in recent years, a substantial progress has been made in the treatment of pulmonary hypertension, it is still a severe disease characterized by poor prognosis, and the search for new drugs remains a priority. Current remedies address mainly the vasoconstrictor/ vasodilator imbalance in the pulmonary circulation, while the causes of the disease are only moderately affected. Recently, the role of receptor and non receptor kinases in pulmonary hypertension has emerged and these targets were extensively considered for the development of new therapeutic strategies. This review discusses the patents on small-molecules targeting kinases involved in the proliferation/apoptosis imbalance, typically present in pulmonary hypertension. METHODS: Bibliographic research for the inventions was carried out using Espacenet and Sci-Finder databases, "pulmonary hypertension and kinases" as research query and the range from 2010 to 2015. Only patents published in English were considered. A qualitative analysis of the contents of each patent was made to examine the reported compounds, the studies performed and the resulting conclusions. RESULTS: The review includes about thirty applications. Moreover, in order to illustrate the pathophisiology of the disease and the mechanisms of the targets, about forty additional papers were reported. Considering that imatinib, a PDGF receptor inhibitor, entered the clinical trials for the treatment of pulmonary hypertension, the first patents were devoted to inhibitors of tyrosine kinase receptors, such as PDGFR and c-Kit. Subsequently, in addition to kinase receptors, the role of other pathways involved in pulmonary hypertension has emerged, and some research groups have focused their attention also on non-receptor kinases. Fifteen patents on this topic reported these new targets and new derivatives. However, in most of the inventions, although the pulmonary hypertension is among the treatable diseases, the compounds were subjected only to antiproliferative assays and not to specific tests on animal models. CONCLUSION: The studies reported in this review confirm the continuous research efforts aimed to identify new targets and new drugs for the treatment of pulmonary hypertension. Several inhibitors of kinase were described. These compounds could inhibit mainly important branching processes and pathological growth of blood vessels, thereby might increase the lifespan of patients.
[Mh] Termos MeSH primário: Inibidores de Proteínas Quinases/química
Receptores Proteína Tirosina Quinases/metabolismo
Bibliotecas de Moléculas Pequenas/química
[Mh] Termos MeSH secundário: Animais
Pressão Sanguínea/efeitos dos fármacos
Seres Humanos
Hipertensão Pulmonar/tratamento farmacológico
Músculo Liso Vascular/citologia
Músculo Liso Vascular/efeitos dos fármacos
Músculo Liso Vascular/metabolismo
Inibidores da Captação de Neurotransmissores/química
Inibidores da Captação de Neurotransmissores/farmacologia
Inibidores da Captação de Neurotransmissores/uso terapêutico
Inibidores de Proteínas Quinases/farmacologia
Inibidores de Proteínas Quinases/uso terapêutico
Receptores Proteína Tirosina Quinases/antagonistas & inibidores
Bibliotecas de Moléculas Pequenas/farmacologia
Bibliotecas de Moléculas Pequenas/uso terapêutico
Vasodilatadores/química
Vasodilatadores/farmacologia
Vasodilatadores/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Neurotransmitter Uptake Inhibitors); 0 (Protein Kinase Inhibitors); 0 (Small Molecule Libraries); 0 (Vasodilator Agents); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170208
[Lr] Data última revisão:
170208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160813
[St] Status:MEDLINE


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[PMID]:27325446
[Au] Autor:Yukawa T; Nakada Y; Sakauchi N; Kamei T; Yamada M; Ohba Y; Fujimori I; Ueno H; Takiguchi M; Kuno M; Kamo I; Nakagawa H; Fujioka Y; Igari T; Ishichi Y; Tsukamoto T
[Ad] Endereço:Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: tomoya.yukawa@takeda.com.
[Ti] Título:Design, synthesis, and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitors - Part 3.
[So] Source:Bioorg Med Chem;24(16):3716-26, 2016 Aug 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Peripheral-selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Here, we describe our medicinal chemistry approach to discover a novel series of highly potent, peripheral-selective, and orally available noradrenaline reuptake inhibitors with a low multidrug resistance protein 1 (MDR1) efflux ratio by cyclization of an amide moiety and introduction of an acidic group. We observed that the MDR1 efflux ratio was correlated with the pKa value of the acidic moiety. The resulting compound 9 exhibited favorable PK profiles, probably because of the effect of intramolecular hydrogen bond, which was supported by a its single-crystal structure. The compound 9, 1-{[(6S,7R)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride, which exhibited peripheral NET-selective inhibition at tested doses in rats by oral administration, increased urethral resistance in a dose-dependent manner.
[Mh] Termos MeSH primário: Inibidores da Captação de Neurotransmissores/química
Inibidores da Captação de Neurotransmissores/farmacologia
Norepinefrina/metabolismo
[Mh] Termos MeSH secundário: Animais
Células CHO
Cricetulus
Cristalografia por Raios X
Avaliação Pré-Clínica de Medicamentos
Feminino
Seres Humanos
Ligações de Hidrogênio
Espectrometria de Massas
Estrutura Molecular
Inibidores da Captação de Neurotransmissores/síntese química
Espectroscopia de Prótons por Ressonância Magnética
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neurotransmitter Uptake Inhibitors); X4W3ENH1CV (Norepinephrine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170808
[Lr] Data última revisão:
170808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160622
[St] Status:MEDLINE


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[PMID]:27255177
[Au] Autor:Yukawa T; Fujimori I; Kamei T; Nakada Y; Sakauchi N; Yamada M; Ohba Y; Ueno H; Takiguchi M; Kuno M; Kamo I; Nakagawa H; Fujioka Y; Igari T; Ishichi Y; Tsukamoto T
[Ad] Endereço:Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: tomoya.yukawa@takeda.com.
[Ti] Título:Design, synthesis, and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitors-Part 2.
[So] Source:Bioorg Med Chem;24(14):3207-17, 2016 Jul 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Peripherally selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Herein, we describe our medicinal chemistry approach to discover peripheral-selective noradrenaline reuptake inhibitors to avert the risk of P-gp-mediated DDI at the blood-brain barrier. We observed that steric shielding of the hydrogen-bond acceptors and donors (HBA and HBD) of compound 1 reduced the multidrug resistance protein 1 (MDR1) efflux ratio; however, the resulting compound 6, a methoxyacetamide derivative, was mainly metabolized by CYP2D6 and CYP2C19 in the in vitro phenotyping study, implying the risk of PK variability based on the genetic polymorphism of the CYPs. Replacement of the hydrogen atom with a deuterium atom in a strategic, metabolically hot spot led to compound 13, which was mainly metabolized by CYP3A4. To our knowledge, this study represents the first report of the effect of deuterium replacement for a major metabolic enzyme. The compound 13, N-{[(6S,7R)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-[(2H(3))methyloxy]acetamide hydrochloride, which exhibited peripheral NET selective inhibition at tested doses in rats, increased urethral resistance in a dose-dependent manner.
[Mh] Termos MeSH primário: Inibidores da Captação de Neurotransmissores/química
Inibidores da Captação de Neurotransmissores/farmacologia
Norepinefrina/metabolismo
[Mh] Termos MeSH secundário: Animais
Células CHO
Cricetinae
Cricetulus
Citocromo P-450 CYP2C19/metabolismo
Citocromo P-450 CYP2D6/metabolismo
Desenho de Drogas
Avaliação Pré-Clínica de Medicamentos
Seres Humanos
Inibidores da Captação de Neurotransmissores/síntese química
Ratos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neurotransmitter Uptake Inhibitors); EC 1.14.14.1 (Cytochrome P-450 CYP2C19); EC 1.14.14.1 (Cytochrome P-450 CYP2D6); X4W3ENH1CV (Norepinephrine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170802
[Lr] Data última revisão:
170802
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160604
[St] Status:MEDLINE


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[PMID]:27052887
[Au] Autor:Zhang F; Shao J; Tian J; Zhong Y; Ye L; Meng X; Liu Q; Wang H
[Ad] Endereço:School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, P.R. China.
[Ti] Título:Antidepressant-like Effects of LPM580153, A Novel Potent Triple Reuptake Inhibitor.
[So] Source:Sci Rep;6:24233, 2016 Apr 07.
[Is] ISSN:2045-2322
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The purpose of this study was to characterize a novel compound, 4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl) ethyl] phenyl 3-nitrophenyl ether, designated LPM580153. We used several well-validated animal models of depression to assess the antidepressant-like activity of LPM580153, followed by a neurotransmitter uptake assay and a corticosterone-induced cell injury model to explore its mechanism of action. In mice, LPM580153 reduced immobility time in the tail suspension test, and in rats subjected to chronic unpredictable mild stress it reversed reductions in body weight gain and ameliorated anhedonia. The neurotransmitter uptake assay results demonstrated that LPM580153 inhibited the uptake of serotonin, norepinephrine and dopamine. Furthermore, LPM580153 protected the SH-SY5Y cells against the cytotoxic activity of corticosterone, an action that might be related to the role of LPM580153 in increasing the protein levels of BDNF, p-ERK1/2, p-AKT, p-CREB and p-mTOR. Together, these findings indicate that LPM580153 is a novel triple reuptake inhibitor with robust antidepressant-like effects.
[Mh] Termos MeSH primário: Anedonia/efeitos dos fármacos
Antidepressivos/farmacologia
Cicloexanóis/farmacologia
Depressão/prevenção & controle
Inibidores da Captação de Neurotransmissores/farmacologia
Fenetilaminas/farmacologia
[Mh] Termos MeSH secundário: Animais
Antidepressivos/química
Transporte Biológico/efeitos dos fármacos
Western Blotting
Fator Neurotrófico Derivado do Encéfalo/metabolismo
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Corticosterona/farmacologia
Cicloexanóis/química
Depressão/metabolismo
Modelos Animais de Doenças
Dopamina/metabolismo
Dopamina/farmacocinética
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Seres Humanos
Masculino
Camundongos
Estrutura Molecular
Neuroblastoma/metabolismo
Neuroblastoma/patologia
Inibidores da Captação de Neurotransmissores/química
Norepinefrina/metabolismo
Norepinefrina/farmacocinética
Fenetilaminas/química
Ratos Sprague-Dawley
Serotonina/metabolismo
Serotonina/farmacocinética
Ganho de Peso/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (4-(2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl)phenyl 3-nitrophenyl ether); 0 (Antidepressive Agents); 0 (Brain-Derived Neurotrophic Factor); 0 (Cyclohexanols); 0 (Neurotransmitter Uptake Inhibitors); 0 (Phenethylamines); 333DO1RDJY (Serotonin); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); VTD58H1Z2X (Dopamine); W980KJ009P (Corticosterone); X4W3ENH1CV (Norepinephrine)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170310
[Lr] Data última revisão:
170310
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160408
[St] Status:MEDLINE
[do] DOI:10.1038/srep24233


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[PMID]:26849844
[Au] Autor:Sramek JJ; Hardy LW; Bieck P; Zamora C; Versavel M; Kharidia J; Grinnell T; Chen YL; Sullivan M; Ding H; Cutler NR
[Ad] Endereço:Worldwide Clinical Trials, Beverly Hills, CA, USA.
[Ti] Título:Exploratory Biomarker Study of the Triple Reuptake Inhibitor SEP-432 Compared to the Dual Reuptake Inhibitor Duloxetine in Healthy Normal Subjects.
[So] Source:CNS Neurosci Ther;22(5):404-12, 2016 May.
[Is] ISSN:1755-5949
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: SEP-432 is a triple monoamine reuptake inhibitor of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), based on in vitro binding studies. We sought evidence that SEP-432 engages these monoamine systems by measuring concentrations of monoamines and/or their main metabolites in cerebrospinal fluid (CSF) and plasma and comparing results to duloxetine, a dual reuptake inhibitor of NE and 5-HT. METHODS: Eighteen healthy normal subjects received either SEP-432 (300 mg/day), duloxetine (60 mg/day), or placebo for 14 days in-clinic (double blind) with CSF and plasma collections at baseline (single lumbar puncture) and Day 14 (24-h CSF and plasma collection). Concentrations of monoamines and their metabolites, as well as pharmacokinetic concentrations of SEP-432 and metabolite, were quantified by liquid chromatography-tandem mass spectrometry. RESULTS: Compared to placebo in the Day 14 area under the curve 24-h (AUC0-24 h ) analysis, SEP-432 significantly (P < 0.05) decreased the NE metabolite dihydroxyphenylglycol (DHPG) in CSF and plasma, decreased 5-HT in plasma, and did not affect DA metabolites, while duloxetine had significant effects on DHPG and 5-HT. Time-matched baseline to Day 14 biomarker comparisons confirmed these findings. CONCLUSION: CSF monoamine biomarkers confirmed central NET activity for SEP-432 and duloxetine's dual reuptake inhibition.
[Mh] Termos MeSH primário: Biomarcadores Farmacológicos/sangue
Biomarcadores Farmacológicos/líquido cefalorraquidiano
Cloridrato de Duloxetina/farmacologia
Neurotransmissores/sangue
Neurotransmissores/líquido cefalorraquidiano
Inibidores da Captação de Neurotransmissores/farmacologia
[Mh] Termos MeSH secundário: Adulto
Monoaminas Biogênicas/sangue
Monoaminas Biogênicas/líquido cefalorraquidiano
Cromatografia Líquida de Alta Pressão
Cicloexanóis/farmacologia
Dimetilaminas/farmacologia
Relação Dose-Resposta a Droga
Método Duplo-Cego
Eletrocardiografia
Feminino
Voluntários Saudáveis
Seres Humanos
Masculino
Metoxi-Hidroxifenilglicol/análogos & derivados
Metoxi-Hidroxifenilglicol/metabolismo
Meia-Idade
Espectrometria de Massas em Tandem
Fatores de Tempo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-methylcyclohexanol); 0 (Biogenic Monoamines); 0 (Biomarkers, Pharmacological); 0 (Cyclohexanols); 0 (Dimethylamines); 0 (Neurotransmitter Agents); 0 (Neurotransmitter Uptake Inhibitors); 534-82-7 (Methoxyhydroxyphenylglycol); 9044SC542W (Duloxetine Hydrochloride); CF5G2G268A (dihydroxyphenylethylene glycol)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170116
[Lr] Data última revisão:
170116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160206
[St] Status:MEDLINE
[do] DOI:10.1111/cns.12513



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