RESUMO
A novel series of EP4 agonists and antagonists have been identified, and then used to validate their potential in the treatment of inflammatory pain. This paper describes these novel ligands and their activity within a number of pre-clinical models of pain, ultimately leading to the identification of the EP4 partial agonist GSK726701A.
Assuntos
Anti-Inflamatórios/química , Isoindóis/química , Receptores de Prostaglandina E Subtipo EP4/agonistas , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Células Sanguíneas/citologia , Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/metabolismo , Dinoprostona/química , Dinoprostona/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Concentração Inibidora 50 , Isoindóis/farmacocinética , Isoindóis/uso terapêutico , Lipopolissacarídeos/farmacologia , Dor/tratamento farmacológico , Dor/patologia , Dor/veterinária , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Ratos , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor, thought to play a role in energy metabolism, glucose homeostasis and microglia-mediated neuroinflammation. A novel benzimidazole series of centrally penetrant PPARγ partial agonists has been identified. The optimization of PPARγ activity and in vivo pharmacokinetics leading to the identification of GSK1997132B a potent, metabolically stable and centrally penetrant PPARγ partial agonist, is described.
Assuntos
Benzimidazóis/farmacologia , Descoberta de Drogas , PPAR gama/antagonistas & inibidores , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Estrutura Molecular , PPAR gama/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We describe the discovery and optimization of a novel series of benzofuran EP(1) antagonists, leading to the identification of 26d, a novel nonacidic EP(1) antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain.