RESUMO
Random screening of compounds in endothelin receptor (ET(A) and ET(B)) binding assays led to the discovery of a new class of pyrazol-5-ol ligands. Characterization of structural features crucial for binding activities of these pyrazol-5-ols, by structure activity-relationship (SAR) studies, allowed us to design a novel class of pyrazole-5-carboxylic acids as more potent ET antagonists.
Assuntos
Ácidos Carboxílicos/metabolismo , Endotelinas/antagonistas & inibidores , Pirazóis/metabolismo , Endotelinas/metabolismo , Relação Estrutura-AtividadeRESUMO
We have previously reported the identification of pyrazole-5-carboxylic acids as a new class of endothelin antagonists from low affinity pyrazol-5-ol ligands, which were obtained by random screening assays. We describe herein the synthesis and the structure activity relationships (SARs) of these pyrazole-5-carboxylic acids with potent ET(A) selective, mixed ET(A)/ET(B) or moderately ET(B) selective antagonist activities.
Assuntos
Ácidos Carboxílicos/síntese química , Endotelinas/antagonistas & inibidores , Pirazóis/química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Relação Estrutura-AtividadeRESUMO
The synthesis and inhibitory activity against MraY of a series of simplified analogues of liposidomycins are described. These compounds were mainly obtained by performing parallel synthesis in the 6'-position of a scaffold that gathers key features found necessary for the binding to MraY. Thus, inhibitory activity was improved from 5300 to 140 nM. This improvement was correlated with the length and lipophilicity of substituents, but was found to be independent of the nature of the chemical bond generated. In addition, some of these inhibitors presented encouraging antibacterial activities.