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1.
J Med Chem ; 46(17): 3581-99, 2003 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-12904063

RESUMO

Substituted phenylpropanoic acid derivatives were prepared as part of a search for subtype-selective human peroxisome proliferator activated receptor alpha (PPARalpha) activators. Structure-activity relationship studies indicated that the nature and the stereochemistry of the substituent at the alpha-position of the head part containing the carboxyl group, the distance between the carboxyl group and the central benzene ring, the linking group between the central benzene ring and the distal benzene ring, and the substituent at the distal hydrophobic tail part of the molecule all play key roles in determining the potency and selectivity of PPAR subtype transactivation. This study has led to the identification of potent and human PPARalpha selective optically active alpha-alkylphenylpropanoic acid derivatives, which will be useful not only as pharmacological tools to investigate the physiology and pathophysiology of PPARalpha but also as candidate drugs for the treatment of altered metabolic homeostasis, such as dyslipidemia, obesity, and diabetes.


Assuntos
Fenilpropionatos/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Animais , Células CHO , Colesterol/sangue , Cricetinae , Ácidos Graxos não Esterificados/sangue , Humanos , Masculino , Modelos Moleculares , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Ativação Transcricional/efeitos dos fármacos , Transfecção
2.
Bioorg Med Chem Lett ; 12(16): 2101-4, 2002 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-12127513

RESUMO

An optically active phenylpropanoic acid derivative, a selective agonist for human peroxisome proliferator-activated receptor alpha, was efficiently prepared in high optical purity by using Evans chiral oxazolidinone technique as a key step.


Assuntos
Fenilpropionatos/síntese química , Fenilpropionatos/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Humanos , Estrutura Molecular , Fenilpropionatos/química
3.
Bioorg Med Chem Lett ; 12(3): 333-5, 2002 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-11814790

RESUMO

Optically active phenylpropanoic acid derivatives [(S)-5, and (R)-5] were prepared, and their affinities for peroxisome proliferator-activated receptor (PPAR)alpha and PPAR gamma were evaluated. Binding assay and cell-based reporter assay indicated that the activity of these compounds is enantio-dependent, and resides exclusively on the (S)-isomer.


Assuntos
Fenilpropionatos/síntese química , Fenilpropionatos/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Cristalografia por Raios X , Humanos , Conformação Molecular , Ligação Proteica , Estereoisomerismo , Relação Estrutura-Atividade , Ativação Transcricional
4.
Bioorg Med Chem Lett ; 12(1): 77-80, 2002 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-11738577

RESUMO

A series of substituted phenylpropanoic acid derivatives was prepared as part of a search for subtype-selective human peroxisome proliferator-activated receptor (PPAR) activators. Structure-activity relationship studies indicated that the substituent at the alpha-position of the carboxyl group plays a key role in determining the potency and the selectivity for PPAR transactivation.


Assuntos
Fenilpropionatos/síntese química , Fenilpropionatos/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Animais , Células COS , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Genes Reporter , Humanos , Fenilpropionatos/química , Isoformas de Proteínas/agonistas , Relação Estrutura-Atividade , Ativação Transcricional/efeitos dos fármacos , Transfecção
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