Design, Synthesis, Biological Evaluation and Pharmacokinetics of Bis(hydroxyphenyl) substituted Azoles, Thiophenes, Benzenes, and Aza-Benzenes as Potent and Selective Nonsteroidal Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1 (17β-HSD1)

Pharmaceutical and Medicinal Chemistry, Saarland University, PO Box 15 11 50, D-66041, Saarbrucken, Germany.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 11/2008; 51(21):6725-39. DOI: 10.1021/jm8006917
Source: PubMed


17beta-Estradiol (E2), the most potent female sex hormone, stimulates the growth of mammary tumors and endometriosis via activation of the estrogen receptor alpha (ERalpha). 17beta-Hydroxysteroid dehydrogenase type 1 (17beta-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 17beta-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 IC 50 values in the low nanomolar range, a high selectivity toward 17beta-HSD2, a low binding affinity to ERalpha, 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 17beta-HSD1 inhibition and the electron density distribution.

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Available from: Yaseen A. Al-Soud, Apr 07, 2014
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    • "It is striking that the substitution pattern (1,4-,1,3-benzene or 2,5-thiophene) does not have a great influence on the activity as it can be expected that depending on the substitution pattern the A-or C-ring will cover a completely different region of the enzyme active site. Because of the interesting activity identified for 6f and due to the fact that the thiophene moiety was discovered to be a very promising heteroaromatic ring in the design of 17b-HSD1 inhibitors [47], it was decided to focus on this class of compounds for further optimization. "
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