RESUMO
In order to develop orally active pure antiestrogens, we incorporated the carboxy-containing side chains into the 7alpha-position of the steroid scaffold and found that 17-keto derivative CH4893237 (12b) functioned as a pure antiestrogen with its oral activity much superior to clinically used pure antiestrogen, ICI182,780. Results from the pharmacokinetic evaluation indicated that the potent antiestrogen activity at oral dosing in mice attributed to both improved absorption from the intestinal wall and metabolic stability in liver.
Assuntos
Moduladores de Receptor Estrogênico/química , Moduladores de Receptor Estrogênico/farmacologia , Administração Oral , Animais , Moduladores de Receptor Estrogênico/administração & dosagem , Moduladores de Receptor Estrogênico/síntese química , Haplorrinos , Camundongos , Estrutura Molecular , Ratos , Esteroides/química , Esteroides/farmacologia , Relação Estrutura-AtividadeRESUMO
In order to search for alternatives to the sulfoxide moiety in the long side chain of pure antiestrogens, several molecules that may interact with water in a fashion similar to ICI164,384 were designed and it was found that compounds with the carboxy, the sulfamide, or the sulfonamide instead of the sulfoxide moiety also functioned as pure antiestrogens. Interestingly, the compound possessing the carboxy moiety showed superior antiestrogen activity compared to ICI182,780 when dosed orally. Results of the pharmacokinetic evaluation indicated that the potent antiestrogen activity at oral dosing attributed to both the improved absorption from the intestinal wall and the metabolic stability of the compound in liver.
