Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Neuropharmacology ; 102: 59-71, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26522434

RESUMO

Metabotropic glutamate receptor 4 (mGluR4) possesses immune modulatory properties in vivo, such that a positive allosteric modulator (PAM) of the receptor confers protection on mice with relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE). ADX88178 is a newly-developed, one such mGluR4 modulator with high selectivity, potency, and optimized pharmacokinetics. Here we found that application of ADX88178 in the RR-EAE model system converted disease into a form of mild-yet chronic-neuroinflammation that remained stable for over two months after discontinuing drug treatment. In vitro, ADX88178 modulated the cytokine secretion profile of dendritic cells (DCs), increasing production of tolerogenic IL-10 and TGF-ß. The in vitro effects required activation of a Gi-independent, alternative signaling pathway that involved phosphatidylinositol-3-kinase (PI3K), Src kinase, and the signaling activity of indoleamine 2,3-dioxygenase 1 (IDO1). A PI3K inhibitor as well as small interfering RNA targeting Ido1-but not pertussis toxin, which affects Gi protein-dependent responses-abrogated the tolerogenic effects of ADX88178-conditioned DCs in vivo. Thus our data indicate that, in DCs, highly selective and potent mGluR4 PAMs such as ADX88178 may activate a Gi-independent, long-lived regulatory pathway that could be therapeutically exploited in chronic autoimmune diseases such as multiple sclerosis.


Assuntos
Células Dendríticas/efeitos dos fármacos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Células Dendríticas/metabolismo , Feminino , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Pirimidinas/farmacologia , RNA Interferente Pequeno , Tiazóis/farmacologia
2.
Org Lett ; 11(9): 1995-7, 2009 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-19354286

RESUMO

The asymmetric total synthesis of the originally proposed structure of gymnangiamide, a cytotoxic pentapeptide isolated from the marine hydroid Gymnangium regae Jaderholm, has been achieved. Key to the synthesis was the use of asymmetric hydrogenation of alpha-substituted beta-ketoesters through dynamic kinetic resolution for the preparation of nonproteinogenic chiral amino acids. The disparity of the NMR spectra between the synthetic material containing the L-serine residue and the natural product required a revision of the proposed structure.


Assuntos
Oligopeptídeos/síntese química , Animais , Hydra/química , Biologia Marinha , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Estereoisomerismo
3.
Eur J Med Chem ; 42(5): 567-79, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17223230

RESUMO

Novel diarylpyrimidines (DAPY), which represent next generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs), were synthesized and their activities against human immunodeficiency virus type I (HIV-1) assessed. Modulations at positions 2 and 6 of the left phenyl ring generated interesting derivatives of TMC278 displaying high potency against wild-type and mutant viruses compared to nevirapine and efavirenz. The pharmacokinetic profile of the best newly synthesized DAPY was evaluated and compared with TMC278 now in phase II clinical trials.


Assuntos
HIV-1/efeitos dos fármacos , Nitrilas/síntese química , Nitrilas/farmacologia , Pirimidinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Animais , Cromatografia Líquida de Alta Pressão , Cães , Feminino , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Pirimidinas/síntese química , Pirimidinas/farmacologia , Ratos , Ratos Wistar , Rilpivirina , Espectrofotometria Ultravioleta
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA