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Pharmacology ; 102(5-6): 244-252, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30134246


BACKGROUND/AIMS: Retinoid-related orphan receptor gamma t (RORγt) is a master regulator of T helper 17 cells that plays a pivotal role in the production of inflammatory cytokines including interleukin (IL)-17. Therefore, RORγt has attracted much attention as a target receptor for the treatment of inflammatory diseases including rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, and psoriasis. This study aims to characterize TAK-828F, a potent and selective RORγt inverse agonist. METHODS: The biochemical properties of TAK-828F were evaluated using Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) binding assay, surface plasmon resonance (SPR) biosensor assay, cofactor recruitment assay, reporter assay, and IL-17 expression assay. RESULTS: TR-FRET binding assay and SPR biosensor assay revealed rapid, reversible, and high affinity binding of TAK-828F to RORγt. The cofactor recruitment assay showed that TAK-828F inhibited the recruitment of steroid receptor coactivator-1 to RORγt. Furthermore, TAK-828F inhibited the transcriptional activity of human and mouse RORγt with selectivity against human RORα and RORß. TAK-828F also suppressed IL-17 production in Jurkat cells, overexpressing human RORγt. CONCLUSION: These favorable properties will be of advantage in the evaluation of TAK-828F in clinical studies for inflammatory diseases. Furthermore, these findings demonstrate that TAK-828F could serve as a pharmacological tool for further studies of RORγt and inflammatory diseases.

Benzofuranos/química , Benzofuranos/farmacologia , Receptores Nucleares Órfãos/agonistas , Sulfonas/química , Sulfonas/farmacologia , Animais , Benzofuranos/farmacocinética , Cromatografia de Afinidade , Transferência Ressonante de Energia de Fluorescência , Humanos , Interleucina-17/metabolismo , Células Jurkat , Cinética , Camundongos , Receptores Nucleares Órfãos/metabolismo , Ligação Proteica , Sulfonas/farmacocinética , Ativação Transcricional
Bioorg Med Chem ; 26(3): 721-736, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29342416


Novel small molecules were synthesized and evaluated as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of inflammatory and autoimmune diseases. A hit compound, 1, was discovered by high-throughput screening of our compound library. The structure-activity relationship (SAR) study of compound 1 showed that the introduction of a chlorine group at the 3-position of 4-cyanophenyl moiety increased the potency and a 3-methylpentane-1,5-diamide linker is favorable for the activity. The carbazole moiety of 1 was also optimized; a quinazolinedione derivative 18i suppressed the increase of IL-17A mRNA level in the lymph node of a rat model of experimental autoimmune encephalomyelitis (EAE) upon oral administration. These results indicate that the novel quinazolinedione derivatives have great potential as orally available small-molecule RORγt inverse agonists for the treatment of Th17-driven autoimmune diseases. A U-shaped bioactive conformation of this chemotype with RORγt protein was also observed.

Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Quinazolinonas/química , Administração Oral , Animais , Sítios de Ligação , Agonismo Inverso de Drogas , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/veterinária , Feminino , Humanos , Concentração Inibidora 50 , Interleucina-17/genética , Interleucina-17/metabolismo , Células Jurkat , Simulação de Acoplamento Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Quinazolinonas/administração & dosagem , Quinazolinonas/metabolismo , Quinazolinonas/farmacologia , Ratos , Ratos Endogâmicos Lew , Solubilidade , Relação Estrutura-Atividade , Células Th17/citologia , Células Th17/efeitos dos fármacos , Células Th17/metabolismo
Bioorg Med Chem ; 26(2): 483-500, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29262987


A series of novel phenylglycinamides as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists were discovered through optimization of a high-throughput screen hit 1. (R)-N-(2-((3,5-Difluoro-4-(trimethylsilyl)phenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methylisoxazole-5-carboxamide (22) was identified as one of the best of these compounds. It displayed higher subtype selectivity and specificity over other nuclear receptors and demonstrated in vivo potency to suppress the transcriptional activity of RORγt in a mouse PD (pharmacodynamic) model upon oral administration.

Descoberta de Drogas , Glicina/análogos & derivados , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Administração Oral , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Glicina/administração & dosagem , Glicina/química , Glicina/farmacologia , Humanos , Células Jurkat , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Animais , Modelos Moleculares , Estrutura Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Relação Estrutura-Atividade
Bioorg Med Chem Lett ; 27(5): 1145-1148, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28174108


We describe a methodology for quick development of fluorescent probes with the desired potency for the target of interest by using a method of parallel synthesis, termed as Parallel Fluorescent Probe Synthesis (Parallel-FPS). BODIPY FL propionic acid 1 is a widely used fluorophore, but it is difficult to prepare a large amount of 1, which hinders its use in parallel synthesis. Optimization of a synthetic scheme enabled us to obtain 50g of 1 in one batch. With this large quantity of 1 in hand, we performed Parallel-FPS of BODIPY FL-labeled ligands for estrogen related receptor-α (ERRα). An initial trial of the parallel synthesis with various linkers provided a potent ligand for ERRα (Reporter IC50=80nM), demonstrating the usefulness of Parallel-FPS.

Compostos de Boro/química , Corantes Fluorescentes/síntese química , Propionatos/química , Ligantes , Receptores de Estrogênio/química
Appl Microbiol Biotechnol ; 89(6): 1929-38, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21069315


4-Hydroxyisoleucine (HIL) found in fenugreek seeds has insulinotropic and anti-obesity effects and is expected to be a novel orally active drug for insulin-independent diabetes. Here, we show that the newly isolated strain Bacillus thuringiensis 2e2 and the closely related strain B. thuringiensis ATCC 35646 operate a novel metabolic pathway for L-isoleucine (L-Ile) via HIL and 2-amino-3-methyl-4-ketopentanoic acid (AMKP). The HIL synthesis was catalyzed stereoselectively by an α-ketoglutaric acid-dependent dioxygenase and to be useful for efficient production of a naturally occurring HIL isomer, (2S,3R,4S)-HIL. The (2S,3R,4S)-HIL was oxidized to (2S,3R)-AMKP by a NAD(+)-dependent dehydrogenase. The metabolic pathway functions as an effective bypass pathway that compensates for the incomplete tricarboxylic acid (TCA) cycle in Bacillus species and also explains how AMKP, a vitamin B(12) antimetabolite with antibiotic activity, is synthesized. These novel findings pave a new way for the commercial production of HIL and also for AMKP.

Bacillus thuringiensis/metabolismo , Vias Biossintéticas/genética , Isoleucina/análogos & derivados , Isoleucina/biossíntese , Bacillus thuringiensis/genética , Coenzimas/metabolismo , Dioxigenases/genética , Dioxigenases/metabolismo , Cetoácidos/metabolismo , NAD/metabolismo , Oxirredução , Oxirredutases/metabolismo , Ácidos Pentanoicos/metabolismo