RESUMO
A series of 5-N,N-disubstituted-5-aminopyrazole-3-carboxylic acids were prepared and found to act as highly potent and selective agonists of the G-Protein Coupled Receptor (GPCR) GPR109b, a low affinity receptor for niacin and some aromatic d-amino acids. Little activity was observed at the highly homologous higher affinity niacin receptor, GPR109a.
Assuntos
Ácidos Carboxílicos/síntese química , Receptores Acoplados a Proteínas G/agonistas , Animais , Aterosclerose/tratamento farmacológico , Células CHO , Ácidos Carboxílicos/farmacologia , Química Farmacêutica/métodos , Cricetinae , Cricetulus , Desenho de Fármacos , Dislipidemias/tratamento farmacológico , Humanos , Ligantes , Lipoproteínas HDL/química , Lipoproteínas LDL/química , Modelos Químicos , Niacina/química , Pirazóis/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores NicotínicosRESUMO
A series of 3-nitro-4-substituted-aminobenzoic acids were prepared and found to act as potent and highly selective agonists of the orphan human GPCR GPR109b, a low affinity receptor for niacin. No activity was observed at the closely homologous high affinity niacin receptor, GPR109a. A second series, comprising 6-amino-substituted nicotinic acids was, also prepared and several analogues showed comparable activity to the nitroaryl series.
Assuntos
Benzoatos/química , Ácidos Nicotínicos/química , Receptores Acoplados a Proteínas G/agonistas , Animais , Benzoatos/agonistas , Benzoatos/metabolismo , Células CHO , Cricetinae , Cricetulus , Humanos , Niacina/metabolismo , Ácidos Nicotínicos/agonistas , Ácidos Nicotínicos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/fisiologia , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/fisiologia , Relação Estrutura-AtividadeRESUMO
A series of 5-alkyl pyrazole-3-carboxylic acids were prepared and found to act as potent and selective agonists of the human GPCR, GPR109a, the high affinity nicotinic acid receptor. No activity was observed at the highly homologous low affinity niacin receptor, GPR109b. A further series of 4-fluoro-5-alkyl pyrazole-3-carboxylic acids were shown to display similar potency. One example from the series was shown to have improved properties in vivo compared to niacin.