RESUMO
A novel series of 5-membered heterocycle-containing phenylpropanoic acid derivatives was discovered as potent GPR120 agonists with low clearance, high oral bioavailability and in vivo antidiabetic activity in rodents.
Assuntos
Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Disponibilidade Biológica , Glicemia/análise , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Desenho de Fármacos , Células HEK293 , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacocinética , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/uso terapêutico , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Camundongos Endogâmicos C57BL , Fenilpropionatos/farmacocinética , Fenilpropionatos/uso terapêutico , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel series of N-pyridyl amides as potent p38alpha kinase inhibitors is described. Based on the structural similarities between the initial hit and a well-known imidazole pyrimidine series of p38alpha inhibitors, potencies within the newly discovered series were quickly improved by installation of an (S)-alpha-methylbenzyl moiety at the 2-position of the pyridine ring. The proposed binding modes of the new series to p38alpha were evaluated against SAR findings and provided rationale for further development of this series of molecules.
Assuntos
Amidas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Amidas/química , Descoberta de Drogas , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
Optimization of a tri-substituted N-pyridyl amide led to the discovery of a new class of potent N-pyrimidyl amide based p38alpha MAP kinase inhibitors. Initial SAR studies led to the identification of 5-dihydrofuran as an optimal hydrophobic group. Additional side chain modifications resulted in the introduction of hydrogen bond interactions. Through extensive SAR studies, analogs bearing free amino groups and alternatives to the parent (S)-alpha-methyl benzyl moiety were identified. These compounds exhibited improved cellular activities and maintained balance between p38alpha and CYP3A4 inhibition.
Assuntos
Amidas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Amidas/química , Desenho de Fármacos , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
Derivatives of the 4-fluorobenzyl dimethylpiperazine-indole class of p38alpha MAP kinase inhibitors are described. Biological evaluation of these compounds focused on maintaining activity while improving pharmacokinetic (PK) properties. Improved properties were observed for structures bearing substitutions on the benzylic methylene.