| Abstract
| - 17β-Estradiol (E2), the most potent female sex hormone, stimulates the growth of mammary tumors and endometriosis via activation of the estrogen receptor α (ERα). 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1), which is responsible for the catalytic reduction of the weakly active estrogen estrone (E1) into E2, is therefore discussed as a novel drug target. Recently, we have discovered a 2,5-bis(hydroxyphenyl) oxazole to be a potent inhibitor of 17β-HSD1. In this paper, further structural optimizations were performed: 39 bis(hydroxyphenyl) azoles, thiophenes, benzenes, and aza-benzenes were synthesized and their biological properties were evaluated. The most promising compounds of this study show enhanced IC50 values in the low nanomolar range, a high selectivity toward 17β-HSD2, a low binding affinity to ERα, a good metabolic stability in rat liver microsomes, and a reasonable pharmacokinetic profile after peroral application. Calculation of the molecular electrostatic potentials revealed a correlation between 17β-HSD1 inhibition and the electron density distribution.
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