RESUMO
The synthesis and biological evaluation of novel pyrazole-3-carboxamide derivatives as CB1 antagonists are described. As a part of eastern amide SAR, various chemically diverse motifs were introduced. In general, a range of modifications were well tolerated. Several molecules with high polar surface area were also identified as potent CB1 receptor antagonists. The in vivo proof of principle for weight loss is exemplified with a lead compound from this series.
Assuntos
Amidas/química , Pirazóis/química , Receptor CB1 de Canabinoide/antagonistas & inibidores , Tetrazóis/química , Administração Oral , Amidas/síntese química , Amidas/farmacologia , Animais , Camundongos , Pirazóis/síntese química , Pirazóis/farmacologia , Ratos , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/farmacologia , Redução de Peso/efeitos dos fármacosRESUMO
The synthesis and biological evaluation of novel pyrazole and imidazole carboxamides as CB1 antagonists are described. As a part of eastern amide SAR, various chemically diverse motifs were introduced on rimonabant template. The central pyrazole core was also replaced with its conformationally constrained motif and imidazole moieties. In general, a range of modifications were well tolerated. Several molecules with low- and sub-nanomolar potencies were identified as potent CB1 receptor antagonists. The in vivo proof of principle for weight loss is demonstrated with a lead compound in DIO mice model.