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[PMID]:28449891
[Au] Autor:Kollb-Sielecka M; Demolis P; Emmerich J; Markey G; Salmonson T; Haas M
[Ad] Endereço:European Medicines Agency (EMA), London, United Kingdom. Electronic address: marta.kollb-sielecka@ema.europa.
[Ti] Título:The European Medicines Agency review of pitolisant for treatment of narcolepsy: summary of the scientific assessment by the Committee for Medicinal Products for Human Use.
[So] Source:Sleep Med;33:125-129, 2017 May.
[Is] ISSN:1878-5506
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:On 31 March 2016, the European Commission issued a decision for a marketing authorisation valid throughout the European Union (EU) for pitolisant (Wakix) for the treatment of narcolepsy with or without cataplexy in adults. Pitolisant is an antagonist/inverse agonist of the human histamine H3 receptor. The dose should be selected using an up-titration scheme depending on individual patient response and tolerance and should not exceed 36 mg/day. The main evidence of efficacy of pitolisant was based on two Phase III clinical trials. The improvement on excessive daytime sleepiness was shown against placebo in the Harmony I study (-3.33 points; 95% confidence interval (CI) [-5.83; -0.83]; p = 0.024) and in Harmony CTP (-3.41 points; 95% CI [-4.95; -1.87]; p < 0.0001). The daily cataplexy rate in Harmony I improved against placebo with a rate ratio (rR) of 0.38 whilst in the Harmony CTP the ratio of improvement on weekly cataplexy rate against placebo was 0.512. The most commonly reported adverse reactions were headache, insomnia and nausea. This article summarizes the scientific review leading to approval of pitolisant in the EU. The assessment report and product information are available on the European Medicines Agency website (http://www.ema.europa.eu).
[Mh] Termos MeSH primário: Narcolepsia/tratamento farmacológico
Piperidinas/uso terapêutico
Receptores Histamínicos H3/efeitos dos fármacos
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Animais
Atenção/efeitos dos fármacos
Cataplexia/tratamento farmacológico
Ensaios Clínicos Fase III como Assunto
Cognição/efeitos dos fármacos
Agonismo Inverso de Drogas
Seres Humanos
Meia-Idade
Piperidinas/administração & dosagem
Piperidinas/efeitos adversos
Piperidinas/metabolismo
Receptores Histamínicos H3/fisiologia
Resultado do Tratamento
Promotores da Vigília/farmacologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Piperidines); 0 (Receptors, Histamine H3); 0 (Wakefulness-Promoting Agents); 4BC83L4PIY (1-(3-(3-(4-chlorophenyl)propoxy)propyl)piperidine)
[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:170429
[St] Status:MEDLINE


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[PMID]:29334795
[Au] Autor:Lazewska D; Kiec-Kononowicz K
[Ad] Endereço:a Department of Technology and Biotechnology of Drugs , Jagiellonian University Medical College , Kraków , Poland.
[Ti] Título:Progress in the development of histamine H receptor antagonists/inverse agonists: a patent review (2013-2017).
[So] Source:Expert Opin Ther Pat;28(3):175-196, 2018 Mar.
[Is] ISSN:1744-7674
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Since years, ligands blocking histamine H receptor (H R) activity (antagonists/inverse agonists) are interesting targets in the search for new cures for CNS disorders. Intensive works done by academic and pharmaceutical company researchers have led to many potent and selective H R antagonists/inverse agonists. Some of them have reached to clinical trials. Areas covered: Patent applications from January 2013 to September 2017 and the most important topics connected with H R field are analysed. Espacenet, Patentscope, Pubmed, GoogleScholar or Cochrane Library online databases were principially used to collect all the materials. Expert opinion: The research interest in histamine H R field is still high although the number of patent applications has decreased during the past 4 years (around 20 publications). Complexity of histamine H R biology e.g. many isoforms, constitutive activity, heteromerization with other receptors (dopamine D , D , adenosine A ) and pharmacology make not easy realization and evaluation of therapeutic potential of anti-H R ligands. First results from clinical trials have verified potential utility of histamine H R antagonist/inverse agonists in some diseases. However, more studies are necessary for better understanding of an involvement of the histaminergic system in CNS-related disorders and helping more ligands approach to clinical trials and the market. Lists of abbreviations: hAChEI - human acetylcholinesterase inhibitor; hBuChEI - human butyrylcholinesterase inhibitor; hMAO - human monoamine oxidase; MAO - monoamine oxidase.
[Mh] Termos MeSH primário: Desenho de Drogas
Agonismo Inverso de Drogas
Antagonistas dos Receptores Histamínicos H3/farmacologia
[Mh] Termos MeSH secundário: Animais
Doenças do Sistema Nervoso Central/tratamento farmacológico
Doenças do Sistema Nervoso Central/fisiopatologia
Seres Humanos
Ligantes
Patentes como Assunto
Receptores Histamínicos H3/efeitos dos fármacos
Receptores Histamínicos H3/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Histamine H3 Antagonists); 0 (Ligands); 0 (Receptors, Histamine H3)
[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:180117
[St] Status:MEDLINE
[do] DOI:10.1080/13543776.2018.1424135


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[PMID]:29253893
[Au] Autor:Chen Y; Zhen W; Guo T; Zhao Y; Liu A; Rubio JP; Krull D; Richardson JC; Lu H; Wang R
[Ad] Endereço:Neuro-immunology Discovery Performance Unit, GSK, Shanghai, China.
[Ti] Título:Histamine Receptor 3 negatively regulates oligodendrocyte differentiation and remyelination.
[So] Source:PLoS One;12(12):e0189380, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Agents promoting oligodendrocyte precursor cell differentiation have the potential to restore halted and/or delayed remyelination in patients with multiple sclerosis. However, few therapeutic targets have been identified. The objective of this study was to identify novel targets for promotion of remyelination and characterize their activity in vitro and in vivo. METHODS: A high-content screening assay with differentiation of primary rat oligodendrocyte precursor cells was used to screen GSK-proprietary annotated libraries for remyelination-promoting compounds. Compounds were further validated in vitro and in vivo models; clinical relevance of target was confirmed in human post-mortem brain sections from patients with MS. RESULTS: Of ~1000 compounds screened, 36 promoted oligodendrocyte precursor cell differentiation in a concentration-dependent manner; seven were histamine receptor-3 (H3R) antagonists. Inverse agonists of H3R but not neutral antagonists promoted oligodendrocyte precursor cell (OPC) differentiation. H3R was expressed throughout OPC differentiation; H3R expression was transiently upregulated on Days 3-5 and subsequently downregulated. H3R gene knockdown in OPCs increased the expression of differentiation markers and the number of mature oligodendrocytes. Overexpression of full-length H3R reduced differentiation marker expression and the number of mature cells. H3R inverse agonist GSK247246 reduced intracellular cyclic AMP (cAMP) and downstream cAMP response element-binding protein (CREB) phosphorylation in a dose-dependent manner. Histone deacetylase (HDAC-1) and Hes-5 were identified as key downstream targets of H3R during OPC differentiation. In the mouse cuprizone/rapamycin model of demyelination, systemic administration of brain-penetrable GSK247246 enhanced remyelination and subsequently protected axons. Finally, we detected high H3R expression in oligodendroglial cells from demyelination lesions in human samples of patients with MS, and validated a genetic association between an exonic single nucleotide polymorphism in HRH3 and susceptibility to multiple sclerosis. CONCLUSIONS: From phenotypic screening to human genetics, we provide evidence for H3R as a novel therapeutic target to promote remyelination in patients with multiple sclerosis.
[Mh] Termos MeSH primário: Esclerose Múltipla/genética
Bainha de Mielina/metabolismo
Oligodendroglia/citologia
Receptores Histamínicos H3/metabolismo
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Encéfalo/patologia
Diferenciação Celular
Proliferação Celular
Glutationa Transferase/metabolismo
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Esclerose Múltipla/tratamento farmacológico
Esclerose Múltipla/metabolismo
Oligodendroglia/metabolismo
Fenótipo
Polimorfismo de Nucleotídeo Único
Prosencéfalo/patologia
Ratos
Receptores Histamínicos H3/genética
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Histamine H3); EC 2.5.1.18 (Glutathione Transferase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171219
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189380


  4 / 1220 MEDLINE  
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[PMID]:28982153
[Au] Autor:Jonczyk J; Malawska B; Bajda M
[Ad] Endereço:Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland.
[Ti] Título:Hybrid approach to structure modeling of the histamine H3 receptor: Multi-level assessment as a tool for model verification.
[So] Source:PLoS One;12(10):e0186108, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The crucial role of G-protein coupled receptors and the significant achievements associated with a better understanding of the spatial structure of known receptors in this family encouraged us to undertake a study on the histamine H3 receptor, whose crystal structure is still unresolved. The latest literature data and availability of different software enabled us to build homology models of higher accuracy than previously published ones. The new models are expected to be closer to crystal structures; and therefore, they are much more helpful in the design of potential ligands. In this article, we describe the generation of homology models with the use of diverse tools and a hybrid assessment. Our study incorporates a hybrid assessment connecting knowledge-based scoring algorithms with a two-step ligand-based docking procedure. Knowledge-based scoring employs probability theory for global energy minimum determination based on information about native amino acid conformation from a dataset of experimentally determined protein structures. For a two-step docking procedure two programs were applied: GOLD was used in the first step and Glide in the second. Hybrid approaches offer advantages by combining various theoretical methods in one modeling algorithm. The biggest advantage of hybrid methods is their intrinsic ability to self-update and self-refine when additional structural data are acquired. Moreover, the diversity of computational methods and structural data used in hybrid approaches for structure prediction limit inaccuracies resulting from theoretical approximations or fuzziness of experimental data. The results of docking to the new H3 receptor model allowed us to analyze ligand-receptor interactions for reference compounds.
[Mh] Termos MeSH primário: Receptores Histamínicos H3/química
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Seres Humanos
Ligantes
Modelos Moleculares
Conformação Proteica
Homologia de Sequência de Aminoácidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); 0 (Receptors, Histamine H3)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171006
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0186108


  5 / 1220 MEDLINE  
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[PMID]:28888822
[Au] Autor:Ledneczki I; Tapolcsányi P; Gábor E; Éles J; Greiner I; Schmidt É; Némethy Z; Kedves RS; Balázs O; Román V; Lévay G; Mahó S
[Ad] Endereço:Chemical Works of Gedeon Richter Plc, H-1475, Budapest P.O. Box 27, Hungary. Electronic address: ledneczki@richter.hu.
[Ti] Título:Discovery of novel steroidal histamine H receptor antagonists/inverse agonists.
[So] Source:Bioorg Med Chem Lett;27(19):4525-4530, 2017 10 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Emerging from an HTS campaign, novel steroid-based histamine H receptor antagonists were identified and characterized. Structural moieties of the hit compounds were combined to improve binding affinities which resulted in compound 4 as lead molecule. During the lead optimization due to the versatile modifications of diamino steroid derivatives, several in vitro potent compounds with subnanomolar binding affinities to histamine H receptors were found. The unfavorable binding to rat muscarinic receptors was successfully reduced by tuning the basicity. Compound 20 showed significant in vivo activity in the rat dipsogenia model and could serve as a pharmacological tool in the future.
[Mh] Termos MeSH primário: Descoberta de Drogas
Agonistas dos Receptores Histamínicos/farmacologia
Antagonistas dos Receptores Histamínicos H3/farmacologia
Receptores Histamínicos H3/metabolismo
[Mh] Termos MeSH secundário: Animais
Relação Dose-Resposta a Droga
Agonistas dos Receptores Histamínicos/síntese química
Agonistas dos Receptores Histamínicos/química
Antagonistas dos Receptores Histamínicos H3/síntese química
Antagonistas dos Receptores Histamínicos H3/química
Seres Humanos
Estrutura Molecular
Ratos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Histamine Agonists); 0 (Histamine H3 Antagonists); 0 (Receptors, Histamine H3)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170911
[St] Status:MEDLINE


  6 / 1220 MEDLINE  
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[PMID]:28797771
[Au] Autor:Lazewska D; Kaleta M; Schwed JS; Karcz T; Mogilski S; Latacz G; Olejarz A; Siwek A; Kubacka M; Lubelska A; Honkisz E; Handzlik J; Filipek B; Stark H; Kiec-Kononowicz K
[Ad] Endereço:Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, ul. Medyczna 9, 30-688 Kraków, Poland. Electronic address: dlazewska@cm-uj.krakow.pl.
[Ti] Título:Biphenyloxy-alkyl-piperidine and azepane derivatives as histamine H receptor ligands.
[So] Source:Bioorg Med Chem;25(20):5341-5354, 2017 Oct 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Novel biphenyloxy-alkyl derivatives of piperidine and azepane were synthesized and evaluated for their binding properties at the human histamine H receptor. Two series of compounds were obtained with a meta- and a para-biphenyl moiety. The alkyl chain spacer contained five and six carbon atoms. The highest affinity among all compounds was shown by 1-(6-(3-phenylphenoxy)hexyl)azepane (13) with a K value of 18nM. Two para-biphenyl derivatives, 1-(5-(4-phenylphenoxy)pentyl)piperidine (14; K =25nM) and 1-(5-(4-phenylphenoxy)pentyl)azepane (16; K =34nM), classified as antagonists in a cAMP accumulation assay (IC =4 and 9nM, respectively), were studied in detail. Compounds 14 and 16 blocked RAMH-induced dipsogenia in rats (ED of 2.72mg/kg and 1.75mg/kg respectively), and showed high selectivity (hH R vs hH R>600-fold) and low toxicity (hERG inhibition: IC >1.70µM; hepatotoxicity IC >12.5µM; non-mutagenic up to 10µM). Furthermore, the metabolic stability was evaluated in vitro on human liver microsomes (HLMs) and/or rat liver microsomes (RLMs). Metabolites produced were analyzed and tentatively identified by UPLC-MS techniques. The results demonstrated easy hydroxylation of the biphenyl ring.
[Mh] Termos MeSH primário: Azepinas/farmacologia
Piperidinas/farmacologia
Receptores Histamínicos H3/metabolismo
[Mh] Termos MeSH secundário: Animais
Azepinas/síntese química
Azepinas/química
Proliferação Celular
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Cobaias
Células HEK293
Células Hep G2
Seres Humanos
Ligantes
Masculino
Estrutura Molecular
Piperidinas/síntese química
Piperidinas/química
Ratos
Ratos Wistar
Receptor Muscarínico M3/antagonistas & inibidores
Receptor Muscarínico M3/metabolismo
Receptores Histamínicos H1/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Azepines); 0 (Ligands); 0 (Piperidines); 0 (Receptor, Muscarinic M3); 0 (Receptors, Histamine H1); 0 (Receptors, Histamine H3); 67I85E138Y (piperidine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170812
[St] Status:MEDLINE


  7 / 1220 MEDLINE  
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[PMID]:28526411
[Au] Autor:Iida T; Yoshikawa T; Kárpáti A; Matsuzawa T; Kitano H; Mogi A; Harada R; Naganuma F; Nakamura T; Yanai K
[Ad] Endereço:Department of Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
[Ti] Título:JNJ10181457, a histamine H3 receptor inverse agonist, regulates in vivo microglial functions and improves depression-like behaviours in mice.
[So] Source:Biochem Biophys Res Commun;488(3):534-540, 2017 Jul 01.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Brain histamine acts as a neurotransmitter and regulates various physiological functions, such as learning and memory, sleep-wake cycles, and appetite regulation. We have recently shown that histamine H3 receptor (H3R) is expressed in primary mouse microglia and has a strong influence on critical functions in microglia, including chemotaxis, phagocytosis, and cytokine secretion in vitro. However, the importance of H3R in microglial activity in vivo remains unknown. Here, we examined the effects of JNJ10181457 (JNJ), a selective and potent H3R inverse agonist, on microglial functions ex vivo and in vivo. First, we injected ATP, which is a typical chemoattractant, into hippocampal slices to investigate the effect of JNJ on chemotaxis. ATP-induced microglial migration toward the injected site was significantly suppressed by JNJ treatment. Next, we examined whether JNJ affected microglial phagocytosis in hippocampal slices and in the prefrontal cortex. Microglial engulfment of dead neurons induced by N-methyl- -aspartate was inhibited in the presence of JNJ. The increase in zymosan particle uptake by activated microglia in the prefrontal cortex was prevented by JNJ administration. Finally, we determined the importance of JNJ in a lipopolysaccharide (LPS)-induced depression model. JNJ reduced the LPS-induced upregulation of microglial pro-inflammatory cytokines and improved depression-like behaviour in the tail-suspension test. These results demonstrate the inhibitory effects of JNJ on chemotaxis, phagocytosis, and cytokine production in microglia inside the brain, and highlight the importance of microglial H3R for brain homeostasis.
[Mh] Termos MeSH primário: Depressão/tratamento farmacológico
Agonistas dos Receptores Histamínicos/farmacologia
Microglia/efeitos dos fármacos
Morfolinas/farmacologia
Piperidinas/farmacologia
Receptores Histamínicos H3/metabolismo
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Camundongos
Microglia/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4-(3-(4-piperidin-1-ylbut-1-ynyl)benzyl)morpholine); 0 (Histamine Agonists); 0 (Morpholines); 0 (Piperidines); 0 (Receptors, Histamine H3)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170521
[St] Status:MEDLINE


  8 / 1220 MEDLINE  
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[PMID]:28498336
[Au] Autor:Siméon FG; Culligan WJ; Lu S; Pike VW
[Ad] Endereço:Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1003, USA. simeonf@mail.nih.gov.
[Ti] Título:C-Labeling of Aryl Ketones as Candidate Histamine Subtype-3 Receptor PET Radioligands through Pd(0)-Mediated C-Carbonylative Coupling.
[So] Source:Molecules;22(5), 2017 May 12.
[Is] ISSN:1420-3049
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Pd(0)-mediated coupling between iodoarenes, [ C]carbon monoxide and aryltributylstannanes has been used to prepare simple model [ C]aryl ketones. Here, we aimed to label four 2-aminoethylbenzofuran chemotype based molecules ([ C] - ) in the carbonyl position, as prospective positron emission tomography (PET) radioligands for the histamine subtype 3 receptor (H3R) by adapting this methodology with use of aryltrimethylstannanes. Radiosynthesis was successfully performed on a platform equipped with a mini-autoclave and a liquid handling robotic arm, within a lead-shielded hot-cell. Candidate radioligands were readily formulated in saline containing ethanol (10%, / ) and ascorbic acid (0.5 mg/10 mL). Yields for preclinical use were in the range of 5-9%, decay-corrected from cyclotron-produced [ C]CO2 and molar activities were >115 GBq/µmol at end of synthesis. Radiochemical purities exceeded >97%.
[Mh] Termos MeSH primário: Radioisótopos de Carbono/química
Marcação por Isótopo
Cetonas/química
Paládio/química
Compostos Radiofarmacêuticos/química
Receptores Histamínicos H3/metabolismo
[Mh] Termos MeSH secundário: Monóxido de Carbono/química
Catálise
Tomografia por Emissão de Pósitrons
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carbon Radioisotopes); 0 (Ketones); 0 (Radiopharmaceuticals); 0 (Receptors, Histamine H3); 5TWQ1V240M (Palladium); 7U1EE4V452 (Carbon Monoxide)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170730
[Lr] Data última revisão:
170730
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170513
[St] Status:MEDLINE


  9 / 1220 MEDLINE  
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[PMID]:28445047
[Au] Autor:Velcicky J; Miltz W; Oberhauser B; Orain D; Vaupel A; Weigand K; Dawson King J; Littlewood-Evans A; Nash M; Feifel R; Loetscher P
[Ad] Endereço:Global Discovery Chemistry, ‡Autoimmunity Transplantation Inflammation, §Musculoskeletal, ∥Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
[Ti] Título:Development of Selective, Orally Active GPR4 Antagonists with Modulatory Effects on Nociception, Inflammation, and Angiogenesis.
[So] Source:J Med Chem;60(9):3672-3683, 2017 May 11.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A novel, selective, and efficacious GPR4 antagonist 13 was developed starting from lead compound 1a. While compound 1a showed promising efficacy in several disease models, its binding to a H receptor as well as a hERG channel prevented it from further development. Therefore, a new round of optimization addressing the key liabilities was performed and led to discovery of compound 13 with an improved profile. Compound 13 showed significant efficacy in the rat antigen induced arthritis as well as in the hyperalgesia and angiogenesis model at a well-tolerated dose of 30 mg/kg.
[Mh] Termos MeSH primário: Inflamação/prevenção & controle
Neovascularização Fisiológica/efeitos dos fármacos
Nociceptividade/efeitos dos fármacos
Receptores Acoplados a Proteínas-G/antagonistas & inibidores
[Mh] Termos MeSH secundário: Administração Oral
Animais
Desenho de Drogas
Feminino
Células HEK293
Seres Humanos
Ratos
Ratos Sprague-Dawley
Receptores Histamínicos H3/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GPR4 protein, human); 0 (Receptors, G-Protein-Coupled); 0 (Receptors, Histamine H3)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170427
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.6b01703


  10 / 1220 MEDLINE  
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[PMID]:28372935
[Au] Autor:Kuder KJ; Lazewska D; Kaleta M; Latacz G; Kottke T; Olejarz A; Karcz T; Fruzinski A; Szczepanska K; Karolak-Wojciechowska J; Stark H; Kiec-Kononowicz K
[Ad] Endereço:Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
[Ti] Título:Synthesis and biological activity of novel tert-amylphenoxyalkyl (homo)piperidine derivatives as histamine H R ligands.
[So] Source:Bioorg Med Chem;25(10):2701-2712, 2017 May 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:As a continuation of our search for novel histamine H receptor ligands a series of twenty new tert-amyl phenoxyalkylamine derivatives (2-21) was synthesized. Compounds of four to eight carbon atoms spacer alkyl chain were evaluated on their binding properties at human histamine H receptor (hH R). The highest affinities were observed for pentyl derivatives 6-8 (K =8.8-23.4nM range) and among them piperidine derivative 6 with K =8.8nM. Structures 6, 7 were also classified as antagonists in cAMP accumulation assay (with EC =157 and 164nM, respectively). Moreover, new compounds were also evaluated for anticonvulsant activity in Antiepileptic Screening Program (ASP) at National Institute of Neurological Disorders and Stroke (USA). Seven compounds (2-4, 9, 11, 12 and 20) showed anticonvulsant activity at maximal electroshock (MES) test in the dose of 30mg/kg at 0.5h. In the subcutaneous pentetrazole (scMET) test compound 4 showed protection at 100 and 300mg/kg dose at mice, however compounds showed high neurotoxicity in rotarod test at used doses. Also, molecular modeling studies were undertaken, to explain affinity of compounds at hH R (taking into the consideration X-ray analysis of compound 18). In order to estimate "drug-likeness" of selected compounds in silico and experimental evaluation of lipophilicity, metabolic stability and cytotoxicity was performed.
[Mh] Termos MeSH primário: Anticonvulsivantes/síntese química
Antagonistas dos Receptores Histamínicos H3/síntese química
Piperidinas/química
Receptores Histamínicos H3/química
[Mh] Termos MeSH secundário: Animais
Anticonvulsivantes/metabolismo
Anticonvulsivantes/toxicidade
Sítios de Ligação
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Eletrochoque
Células HEK293
Antagonistas dos Receptores Histamínicos H3/metabolismo
Antagonistas dos Receptores Histamínicos H3/toxicidade
Seres Humanos
Masculino
Camundongos
Simulação de Acoplamento Molecular
Neurônios/efeitos dos fármacos
Piperidinas/metabolismo
Piperidinas/toxicidade
Ligação Proteica
Estrutura Terciária de Proteína
Ratos
Ratos Sprague-Dawley
Receptores Histamínicos H3/metabolismo
Solubilidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticonvulsants); 0 (Histamine H3 Antagonists); 0 (Piperidines); 0 (Receptors, Histamine H3)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170426
[Lr] Data última revisão:
170426
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170405
[St] Status:MEDLINE



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