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 , TransfecçãoRESUMO
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/químicaRESUMO
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 TranscricionalRESUMO
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.