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Pesquisa : D27.505.389.500.503 [Categoria DeCS]
Referências encontradas : 1076 [refinar]
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[PMID]:29335207
[Au] Autor:Kim SM; Lee M; Lee SY; Lee SM; Kim EJ; Kim JS; Ann J; Lee J; Lee J
[Ad] Endereço:R&D Center, TiumBio Company Ltd., Seongnam-si, Gyeonggi-do, 13493, South Korea.
[Ti] Título:Synthesis and biological evaluation of 3-(2-aminoethyl) uracil derivatives as gonadotropin-releasing hormone (GnRH) receptor antagonists.
[So] Source:Eur J Med Chem;145:413-424, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:We investigated a series of uracil analogues by introducing various substituents on the phenyl ring of the N-3 aminoethyl side chain and evaluated their antagonistic activity against human gonadotropin-releasing hormone (GnRH) receptors. Analogues with substituents at the ortho or meta position demonstrated potent in vitro antagonistic activity. Specifically, the introduction of a 2-OMe group enhanced nuclear factor of activated T-cells (NFAT) inhibition up to 6-fold compared to the unsubstituted analogue. We identified compound 12c as a highly potent GnRH antagonist with moderate CYP inhibition. Compound 12c showed potent and prolonged LH suppression after a single dose was orally administered in castrated monkeys compared to a known antagonist, Elagolix. We believe that our SAR study offers useful insights to design GnRH antagonists as a potential treatment option for endometriosis.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP3A/farmacologia
Citocromo P-450 CYP3A/metabolismo
Receptores LHRH/antagonistas & inibidores
Uracila/farmacologia
[Mh] Termos MeSH secundário: Animais
Inibidores do Citocromo P-450 CYP3A/administração & dosagem
Inibidores do Citocromo P-450 CYP3A/química
Relação Dose-Resposta a Droga
Seres Humanos
Hormônio Luteinizante/antagonistas & inibidores
Hormônio Luteinizante/sangue
Macaca fascicularis
Estrutura Molecular
Relação Estrutura-Atividade
Uracila/análogos & derivados
Uracila/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Receptors, LHRH); 56HH86ZVCT (Uracil); 9002-67-9 (Luteinizing Hormone); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180117
[St] Status:MEDLINE


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[PMID]:28734977
[Au] Autor:Castrignanò S; D'Avino S; Di Nardo G; Catucci G; Sadeghi SJ; Gilardi G
[Ad] Endereço:Department of Life Sciences and Systems Biology, University of Torino, Via Accademia Albertina 13, Torino, Italy.
[Ti] Título:Modulation of the interaction between human P450 3A4 and B. megaterium reductase via engineered loops.
[So] Source:Biochim Biophys Acta;1866(1):116-125, 2018 01.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Chimerogenesis involving cytochromes P450 is a successful approach to generate catalytically self-sufficient enzymes. However, the connection between the different functional modules should allow a certain degree of flexibility in order to obtain functional and catalytically efficient proteins. We previously applied the molecular Lego approach to develop a chimeric P450 3A4 enzyme linked to the reductase domain of P450 BM3 (BMR). Three constructs were designed with the connecting loop containing no glycine, 3 glycine or 5 glycine residues and showed a different catalytic activity and coupling efficiency. Here we investigate how the linker affects the ability of P450 3A4 to bind substrates and inhibitors. We measure the electron transfer rates and the catalytic properties of the enzyme also in the presence of ketoconazole as inhibitor. The data show that the construct 3A4-5GLY-BMR with the longest loop better retains the binding ability and cooperativity for testosterone, compared to P450 3A4. In both 3A4-3GLY-BMR and 3A4-5GLY-BMR, the substrate induces an increase in the first electron transfer rate and a shorter lag phase related to a domain rearrangements, when compared to the construct without Gly. These data are consistent with docking results and secondary structure predictions showing a propensity to form helical structures in the loop of the 3A4-BMR and 3A4-3GLY-BMR. All three chimeras retain the ability to bind the inhibitor ketoconazole and show an IC comparable with those reported for the wild type protein. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone.
[Mh] Termos MeSH primário: Bacillus megaterium/genética
Proteínas de Bactérias/química
Inibidores do Citocromo P-450 CYP3A/química
Citocromo P-450 CYP3A/química
Cetoconazol/química
NADPH-Ferri-Hemoproteína Redutase/química
Proteínas Recombinantes de Fusão/química
[Mh] Termos MeSH secundário: Bacillus megaterium/enzimologia
Proteínas de Bactérias/antagonistas & inibidores
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Sítios de Ligação
Citocromo P-450 CYP3A/genética
Citocromo P-450 CYP3A/metabolismo
Inibidores do Citocromo P-450 CYP3A/metabolismo
Expressão Gênica
Seres Humanos
Cetoconazol/metabolismo
Cinética
Ligantes
Simulação de Acoplamento Molecular
NADPH-Ferri-Hemoproteína Redutase/antagonistas & inibidores
NADPH-Ferri-Hemoproteína Redutase/genética
NADPH-Ferri-Hemoproteína Redutase/metabolismo
Ligação Proteica
Conformação Proteica em alfa-Hélice
Conformação Proteica em Folha beta
Engenharia de Proteínas
Domínios e Motivos de Interação entre Proteínas
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/metabolismo
Relação Estrutura-Atividade
Especificidade por Substrato
Testosterona/química
Testosterona/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Ligands); 0 (Recombinant Fusion Proteins); 3XMK78S47O (Testosterone); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A); EC 1.6.2.4 (NADPH-Ferrihemoprotein Reductase); R9400W927I (Ketoconazole)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170724
[St] Status:MEDLINE


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[PMID]:28471569
[Au] Autor:Wasserstrum Y; Raanani P; Kornowski R; Iakobishvili Z
[Ad] Endereço:Department of Cardiology, Rabin Medical Center (Beilinson Campus), Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel.
[Ti] Título:Concomitant Treatment with Ibrutinib and Amiodarone Causing Reversible Heart Failure Syndrome.
[So] Source:Isr Med Assoc J;18(7):433-434, 2016 Jul.
[Is] ISSN:1565-1088
[Cp] País de publicação:Israel
[La] Idioma:eng
[Mh] Termos MeSH primário: Amiodarona/efeitos adversos
Fibrilação Atrial/induzido quimicamente
Pirazóis/efeitos adversos
Pirimidinas/efeitos adversos
[Mh] Termos MeSH secundário: Idoso
Amiodarona/administração & dosagem
Inibidores do Citocromo P-450 CYP3A/administração & dosagem
Interações Medicamentosas
Insuficiência Cardíaca/induzido quimicamente
Seres Humanos
Masculino
Pirazóis/administração & dosagem
Pirimidinas/administração & dosagem
Síndrome
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP3A Inhibitors); 0 (PCI 32765); 0 (Pyrazoles); 0 (Pyrimidines); N3RQ532IUT (Amiodarone)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE


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[PMID]:28764083
[Au] Autor:Basheer L; Schultz K; Guttman Y; Kerem Z
[Ad] Endereço:Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel. Electronic address: Loai.basheer@mail.huji.ac.il.
[Ti] Título:In silico and in vitro inhibition of cytochrome P450 3A by synthetic stilbenoids.
[So] Source:Food Chem;237:895-903, 2017 Dec 15.
[Is] ISSN:0308-8146
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Inhibition of cytochrome P450 3A4 (CYP3A4), the major drug metabolizing enzyme, by dietary compounds has recently attracted increased attention. Evaluating the potency of the many known inhibitory compounds is a tedious and time consuming task, yet it can be achieved using computing tools. Here, CDOCKER and Glide served to design model inhibitors in order to characterize molecular features of an inhibitor. Assessing nitro-stilbenoids, both approaches suggested nitrostilbene to be a weaker inhibitor of CYP3A4 than resveratrol, and stronger than dimethoxy-nitrostilbene. Nitrostilbene and resveratrol, but not dimethoxy-nitrostilbene, engage electrostatic interactions in the enzyme cavity, and with the haem. In vitro assessment of the inhibitory capacity supported the in silico predictions, suggesting that evaluating the electrostatic interactions of a compound with the prosthetic group allows the prediction of inhibitory potency. Since both programs yielded related results, it is suggested that for CYP3A4, computing tools may allow rapid identification of potent dietary inhibitors.
[Mh] Termos MeSH primário: Citocromo P-450 CYP3A/metabolismo
[Mh] Termos MeSH secundário: Inibidores do Citocromo P-450 CYP3A
Seres Humanos
Microssomos Hepáticos
Estilbenos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Stilbenes); EC 1.14.14.1 (Cytochrome P-450 CYP3A)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170803
[St] Status:MEDLINE


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[PMID]:28699740
[Au] Autor:Okawa T; Aramaki Y; Yamamoto M; Kobayashi T; Fukumoto S; Toyoda Y; Henta T; Hata A; Ikeda S; Kaneko M; Hoffman ID; Sang BC; Zou H; Kawamoto T
[Ad] Endereço:Shonan Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd. , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
[Ti] Título:Design, Synthesis, and Evaluation of the Highly Selective and Potent G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure.
[So] Source:J Med Chem;60(16):6942-6990, 2017 Aug 24.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of ß-adrenergic signaling in vitro studies. Hydrazone derivative 5 and 1,2,4-triazole derivative 24a were identified as hit compounds by HTS. New scaffold generation and SAR studies of all parts resulted in a 4-methyl-1,2,4-triazole derivative with an N-benzylcarboxamide moiety with highly potent activity toward GRK2 and selectivity over other kinases. In terms of subtype selectivity, these compounds showed enough selectivity against GRK1, 5, 6, and 7 with almost equipotent inhibition to GRK3. Our medicinal chemistry efforts led to the discovery of 115h (GRK2 IC = 18 nM), which was obtained the cocrystal structure with human GRK2 and an inhibitor of GRK2 that potentiates ß-adrenergic receptor (ßAR)-mediated cAMP accumulation and prevents internalization of ßARs in ß2AR-expressing HEK293 cells treated with isoproterenol. Therefore, 115h appears to be a novel class of therapeutic for heart failure treatment.
[Mh] Termos MeSH primário: Quinase 2 de Receptor Acoplado a Proteína G/antagonistas & inibidores
Insuficiência Cardíaca/tratamento farmacológico
Inibidores de Proteínas Quinases/farmacologia
Piridinas/farmacologia
Triazóis/farmacologia
meta-Aminobenzoatos/farmacologia
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Citocromo P-450 CYP3A/metabolismo
Inibidores do Citocromo P-450 CYP3A/síntese química
Inibidores do Citocromo P-450 CYP3A/química
Inibidores do Citocromo P-450 CYP3A/farmacologia
Desenho de Drogas
Células HEK293
Ensaios de Triagem em Larga Escala
Seres Humanos
Hidrazonas/síntese química
Hidrazonas/química
Hidrazonas/farmacologia
Proteína Quinase C-alfa/antagonistas & inibidores
Inibidores de Proteínas Quinases/síntese química
Inibidores de Proteínas Quinases/química
Piridinas/síntese química
Piridinas/química
Receptores Adrenérgicos beta/metabolismo
Relação Estrutura-Atividade
Triazóis/síntese química
Triazóis/química
meta-Aminobenzoatos/síntese química
meta-Aminobenzoatos/química
Quinases Associadas a rho/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3-(((4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)-N-(2-(trifluoromethyl)benzyl)benzamide); 0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Hydrazones); 0 (Protein Kinase Inhibitors); 0 (Pyridines); 0 (Receptors, Adrenergic, beta); 0 (Triazoles); 0 (meta-Aminobenzoates); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A); EC 2.7.11.1 (ROCK2 protein, human); EC 2.7.11.1 (rho-Associated Kinases); EC 2.7.11.13 (Protein Kinase C-alpha); EC 2.7.11.15 (ADRBK1 protein, human); EC 2.7.11.16 (G-Protein-Coupled Receptor Kinase 2)
[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:170713
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00443


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[PMID]:28682065
[Au] Autor:Swain NA; Batchelor D; Beaudoin S; Bechle BM; Bradley PA; Brown AD; Brown B; Butcher KJ; Butt RP; Chapman ML; Denton S; Ellis D; Galan SRG; Gaulier SM; Greener BS; de Groot MJ; Glossop MS; Gurrell IK; Hannam J; Johnson MS; Lin Z; Markworth CJ; Marron BE; Millan DS; Nakagawa S; Pike A; Printzenhoff D; Rawson DJ; Ransley SJ; Reister SM; Sasaki K; Storer RI; Stupple PA; West CW
[Ti] Título:Discovery of Clinical Candidate 4-[2-(5-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide (PF-05089771): Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of Na 1.7.
[So] Source:J Med Chem;60(16):7029-7042, 2017 Aug 24.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective Na 1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective Na 1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.
[Mh] Termos MeSH primário: Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo
Éteres Fenílicos/farmacologia
Sulfonamidas/farmacologia
Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular
Citocromo P-450 CYP2C9/metabolismo
Inibidores do Citocromo P-450 CYP2C9/síntese química
Inibidores do Citocromo P-450 CYP2C9/química
Inibidores do Citocromo P-450 CYP2C9/farmacocinética
Inibidores do Citocromo P-450 CYP2C9/farmacologia
Citocromo P-450 CYP3A/metabolismo
Inibidores do Citocromo P-450 CYP3A/síntese química
Inibidores do Citocromo P-450 CYP3A/química
Inibidores do Citocromo P-450 CYP3A/farmacocinética
Inibidores do Citocromo P-450 CYP3A/farmacologia
Desenho de Drogas
Seres Humanos
Microssomos Hepáticos/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.7/química
Éteres Fenílicos/síntese química
Éteres Fenílicos/química
Éteres Fenílicos/farmacocinética
Relação Estrutura-Atividade
Sulfonamidas/síntese química
Sulfonamidas/química
Sulfonamidas/farmacocinética
Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química
Bloqueadores do Canal de Sódio Disparado por Voltagem/química
Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2C9 Inhibitors); 0 (Cytochrome P-450 CYP3A Inhibitors); 0 (NAV1.7 Voltage-Gated Sodium Channel); 0 (PF-05089771); 0 (Phenyl Ethers); 0 (SCN9A protein, human); 0 (Sulfonamides); 0 (Voltage-Gated Sodium Channel Blockers); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A)
[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:170707
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00598


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[PMID]:28671458
[Au] Autor:Ho SY; Alam J; Jeyaraj DA; Wang W; Lin GR; Ang SH; Tan ESW; Lee MA; Ke Z; Madan B; Virshup DM; Ding LJ; Manoharan V; Chew YS; Low CB; Pendharkar V; Sangthongpitag K; Hill J; Keller TH; Poulsen A
[Ad] Endereço:Experimental Therapeutics Centre , 31 Biopolis Way, No. 03-01 Nanos, 138669, Singapore.
[Ti] Título:Scaffold Hopping and Optimization of Maleimide Based Porcupine Inhibitors.
[So] Source:J Med Chem;60(15):6678-6692, 2017 Aug 10.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Porcupine is an O-acyltransferase that regulates Wnt secretion. Inhibiting porcupine may block the Wnt pathway which is often dysregulated in various cancers. Consequently porcupine inhibitors are thought to be promising oncology therapeutics. A high throughput screen against porcupine revealed several potent hits that were confirmed to be Wnt pathway inhibitors in secondary assays. We developed a pharmacophore model and used the putative bioactive conformation of a xanthine inhibitor for scaffold hopping. The resulting maleimide scaffold was optimized to subnanomolar potency while retaining good physical druglike properties. A preclinical development candidate was selected for which extensive in vitro and in vivo profiling is reported.
[Mh] Termos MeSH primário: Aciltransferases/antagonistas & inibidores
Antineoplásicos/farmacologia
Maleimidas/farmacologia
Proteínas de Membrana/antagonistas & inibidores
Piridazinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/administração & dosagem
Antineoplásicos/síntese química
Antineoplásicos/farmacocinética
Linhagem Celular Tumoral
Inibidores do Citocromo P-450 CYP1A2/administração & dosagem
Inibidores do Citocromo P-450 CYP1A2/síntese química
Inibidores do Citocromo P-450 CYP1A2/farmacocinética
Inibidores do Citocromo P-450 CYP1A2/farmacologia
Inibidores do Citocromo P-450 CYP2D6/administração & dosagem
Inibidores do Citocromo P-450 CYP2D6/síntese química
Inibidores do Citocromo P-450 CYP2D6/farmacocinética
Inibidores do Citocromo P-450 CYP2D6/farmacologia
Inibidores do Citocromo P-450 CYP3A/administração & dosagem
Inibidores do Citocromo P-450 CYP3A/síntese química
Inibidores do Citocromo P-450 CYP3A/farmacocinética
Inibidores do Citocromo P-450 CYP3A/farmacologia
Feminino
Células HEK293
Ensaios de Triagem em Larga Escala
Seres Humanos
Maleimidas/administração & dosagem
Maleimidas/síntese química
Maleimidas/farmacocinética
Camundongos Endogâmicos BALB C
Camundongos Nus
Microssomos Hepáticos/metabolismo
Piridazinas/administração & dosagem
Piridazinas/síntese química
Piridazinas/farmacocinética
Ratos
Relação Estrutura-Atividade
Via de Sinalização Wnt
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-(6-cyclopropyl-5,7-dioxo-2,3,4,5,6,7-hexahydro-1H-pyrrolo(3,4-b)pyridin-1-yl)-N-(6-(pyridin-3-yl)pyridazin-3-yl)acetamide); 0 (Antineoplastic Agents); 0 (Cytochrome P-450 CYP1A2 Inhibitors); 0 (Cytochrome P-450 CYP2D6 Inhibitors); 0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Maleimides); 0 (Membrane Proteins); 0 (Pyridazines); EC 2.3.- (Acyltransferases); EC 2.3.1.- (PORCN protein, human); EC 2.3.1.- (Porcn protein, mouse)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170704
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00662


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[PMID]:28659160
[Au] Autor:Jamshidfar S; Ardakani YH; Lavasani H; Rouini M
[Ad] Endereço:Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
[Ti] Título:Inhibition of mirtazapine metabolism by Ecstasy (MDMA) in isolated perfused rat liver model.
[So] Source:Daru;25(1):16, 2017 Jun 28.
[Is] ISSN:2008-2231
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Nowadays MDMA (3,4-methylendioxymethamphetamine), known as ecstasy, is widely abused among the youth because of euphoria induction in acute exposure. However, abusers are predisposed to depression in chronic consumption of this illicit compound. Mirtazapine (MRZ), an antidepressant agent, may be prescribed in MDMA-induced depression. MRZ is extensively metabolized in liver by CYP450 isoenzymes. 8-hydroxymirtazapine (8-OH) is mainly produced by CYP2D6. N-desmethylmirtazapine (NDES) is generated by CYP3A4. MDMA is also metabolized by the mentioned isoenzymes and demonstrates mechanism-based inhibition (MBI) in association with CYP2D6. Several studies revealed that MDMA showed inhibitory effects on CYP3A4. In the present study, our aim was to evaluate the impact of MDMA on the metabolism of MRZ in liver. Therefore, isolated perfused rat liver model was applied as our model of choice in this assessment. METHODS: The subjects of the study were categorized into two experimental groups. Rats in the control group received MRZ-containing Krebs-Henselit buffer (1 µg/ml). Rats in the treatment group received aqueous solution of 1 mg/ml MDMA (3 mg/kg) intraperitoneally 1 hour before receiving MRZ. Perfusate samples were analyzed by HPLC. RESULTS: Analyses of perfusate samples showed 80% increase in the parent drug concentrations and 50% decrease in the concentrations of both metabolites in our treatment group compared to the control group. In the treatment group compared to the control group, AUC of the parent drug demonstrated 50% increase and AUC of 8-OH and NDES showed 70% and 60% decrease, respectively. Observed decrease in metabolic ratios were 83% and 79% for 8-OH and NDES in treatment group compared to control group, respectively. Hepatic clearance (CL ) and intrinsic clearance (Cl ) showed 20% and 60% decrease in treatment group compared to control group. CONCLUSION: All findings prove the inhibitory effects of ecstasy on both CYP2D6 and CYP3A4 hepatic isoenzymes. In conclusion, this study is the first investigation of MRZ metabolism in presence of MDMA in isolated perfused rat liver model.
[Mh] Termos MeSH primário: Antidepressivos/metabolismo
Fígado/metabolismo
Mianserina/análogos & derivados
N-Metil-3,4-Metilenodioxianfetamina/farmacologia
[Mh] Termos MeSH secundário: Animais
Citocromo P-450 CYP2D6/metabolismo
Inibidores do Citocromo P-450 CYP2D6/farmacologia
Citocromo P-450 CYP3A/metabolismo
Inibidores do Citocromo P-450 CYP3A/farmacologia
Fígado/efeitos dos fármacos
Masculino
Mianserina/antagonistas & inibidores
Mianserina/metabolismo
N-Metil-3,4-Metilenodioxianfetamina/efeitos adversos
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antidepressive Agents); 0 (Cytochrome P-450 CYP2D6 Inhibitors); 0 (Cytochrome P-450 CYP3A Inhibitors); 250PJI13LM (Mianserin); A051Q2099Q (mirtazapine); EC 1.14.14.1 (Cytochrome P-450 CYP2D6); EC 1.14.14.1 (Cytochrome P-450 CYP3A); KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170630
[St] Status:MEDLINE
[do] DOI:10.1186/s40199-017-0183-z


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[PMID]:28571685
[Au] Autor:Rasmussen MK; Daujat-Chavanieu M; Gerbal-Chaloin S
[Ad] Endereço:IRMB, INSERM, University of Montpellier, Montpellier, F-34290, France; Department of Food Science, Aarhus University, Tjele, Denmark. Electronic address: Martink.rasmussen@food.au.dk.
[Ti] Título:Activation of the aryl hydrocarbon receptor decreases rifampicin-induced CYP3A4 expression in primary human hepatocytes and HepaRG.
[So] Source:Toxicol Lett;277:1-8, 2017 Aug 05.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The role of the cross-talk between nuclear receptors in the regulation of Cytochrome P450 expression in the liver is well-documented. Most studies have focused on the cross-talk between the pregnane X receptor (PXR) and other receptors, such as the constitutive androstane receptor. However, cross-talk between PXRs and aryl hydrocarbon receptors (AhRs) has also been suggested, but reports regarding this cross-talk are conflicting. In the present study, we treated HepaRG and primary human hepatocytes (PHHs) with both a strong (TCDD) and weak (3-methylindole; 3MI) AhR activator to investigate their impact on PXR-regulated expression of CYP3A4. Moreover, we investigated the effect of co-activation of PXR, using rifampicin, and AhR, using TCDD and 3MI, on the regulation of CYP3A4 induction. We also investigated whether knockdown of AhR using siRNA affected the basal expression of PXR and CYP3A4 and induction of CYP3A4 by rifampicin, TCDD and 3MI. The results showed that the treatment of HepaRG cells, but not of PHHs, with AhR activators decreased mRNA expression of CYP3A4 and PXR. Moreover, in both HepaRG and PHHs, AhR activation decreased rifampicin-induced expression of CYP3A4 mRNA. Knock-down of AhR in PHHs increased both basal and rifampicin-induced expression of CYP3A4 mRNA. In conclusion, the presented results suggested that the cross-talk between PXR and AhR plays a role in the regulation of CYP3A4 gene expression.
[Mh] Termos MeSH primário: Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas
Citocromo P-450 CYP3A/biossíntese
Hepatócitos/efeitos dos fármacos
Dibenzodioxinas Policloradas/toxicidade
Receptores de Hidrocarboneto Arílico/agonistas
Rifampina/farmacologia
Células-Tronco/efeitos dos fármacos
[Mh] Termos MeSH secundário: Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo
Citocromo P-450 CYP3A/genética
Inibidores do Citocromo P-450 CYP3A
Relação Dose-Resposta a Droga
Indução Enzimática
Hepatócitos/enzimologia
Seres Humanos
Cultura Primária de Células
Interferência de RNA
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Receptor Cross-Talk/efeitos dos fármacos
Receptores de Hidrocarboneto Arílico/genética
Receptores de Hidrocarboneto Arílico/metabolismo
Receptores de Esteroides/agonistas
Receptores de Esteroides/genética
Receptores de Esteroides/metabolismo
Transdução de Sinais
Escatol/toxicidade
Células-Tronco/enzimologia
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AHR protein, human); 0 (Basic Helix-Loop-Helix Transcription Factors); 0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Polychlorinated Dibenzodioxins); 0 (RNA, Messenger); 0 (Receptors, Aryl Hydrocarbon); 0 (Receptors, Steroid); 0 (pregnane X receptor); 9W945B5H7R (Skatole); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A); VJT6J7R4TR (Rifampin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170603
[St] Status:MEDLINE


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[PMID]:28550055
[Au] Autor:Sato T; Mishima E; Mano N; Abe T; Yamaguchi H
[Ad] Endereço:Department of Pharmaceutical Sciences, Tohoku University Hospital (T.S., N.M., H.Y.); Division of Nephrology, Endocrinology, and Vascular Medicine, Graduate School of Medicine (E.M., T.A.); Division of Medical Science, Graduate School of Biomedical Engineering (T.A.); Department of Clinical Biology
[Ti] Título:Potential Drug Interactions Mediated by Renal Organic Anion Transporter OATP4C1.
[So] Source:J Pharmacol Exp Ther;362(2):271-277, 2017 Aug.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Organic anion-transporting polypeptide 4C1 (OATP4C1) is an organic anion transporter expressed in the basolateral membrane of the renal proximal tubules. It plays a major role in the urinary excretion of both exogenous drugs and endogenous compounds. Our previous studies have indicated the importance of OATP4C1 in pathologic and physiologic conditions; however, the majority of its pharmacologic characteristics remained unclear. Therefore, to provide essential information for clinical drug therapy decisions and drug development, we clarified drug interactions mediated by OATP4C1. To elucidate potential drug interactions via OATP4C1, we screened 53 representative drugs commonly used in clinical settings. Next, we evaluated the IC values of drugs that inhibited OATP4C1 by more than 50%. To apply our results to clinical settings, we calculated the drug-drug interaction (DDI) indices. The screening analysis using an OATP4C1-expressing cell system demonstrated that 22 out of 53 therapeutic drugs inhibited OATP4C1-mediated triiodothyronine transport. In particular, OATP4C1-mediated transport was strongly inhibited by 10 drugs. The IC values of 10 drugs-nicardipine, spironolactone, fluvastatin, crizotinib, levofloxacin, clarithromycin, ritonavir, saquinavir, quinidine, and verapamil-obtained in this study were 51, 53, 41, 24, 420, 200, 8.5, 4.3, 100, and 110 M, respectively. The IC values of these drugs were higher than the plasma concentrations obtained in clinical practice. However, ritonavir showed the highest DDI index (1.9) for OATP4C1, suggesting that it may strongly influence this transporter and thus cause drug interactions seen in clinical settings. Our finding gives new insight into the role of OATP4C1 in clinical DDIs.
[Mh] Termos MeSH primário: Interações Medicamentosas/fisiologia
Transportadores de Ânions Orgânicos/metabolismo
Preparações Farmacêuticas/metabolismo
[Mh] Termos MeSH secundário: Animais
Inibidores do Citocromo P-450 CYP3A/metabolismo
Inibidores do Citocromo P-450 CYP3A/farmacologia
Cães
Relação Dose-Resposta a Droga
Células Madin Darby de Rim Canino
Ritonavir/metabolismo
Ritonavir/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Organic Anion Transporters); 0 (Pharmaceutical Preparations); 0 (SLCO4C1 protein, human); O3J8G9O825 (Ritonavir)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170528
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.117.241703



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