Discovery of thiochroman derivatives bearing a carboxy-containing side chain as orally active pure antiestrogens

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.

Graphical abstractThiochroman derivatives bearing the carboxy moiety in the long side chain exhibited remarkable antiestrogen activity when administered orally.Figure optionsDownload full-size imageDownload as PowerPoint slide