Selective Dual Inhibitors of CYP19 and CYP11B2: Targeting Cardiovascular Diseases Hiding in the Shadow of Breast Cancer

Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2-3, P.O. Box 151150, D-66123 Saarbrücken, Germany.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 08/2012; 55(16):7080-9. DOI: 10.1021/jm3004637
Source: PubMed


Postmenopausal women are at high risk for cardiovascular diseases because of the estrogen deficiency. As for postmenopausal breast cancer patients, this risk is even higher due to inhibition of estrogens biosyntheses in peripheral tissue by the aromatase (CYP19) inhibitors applied. Because estrogen deficiency results in significantly elevated aldosterone levels, which are a major cause of cardiovascular diseases, dual inhibition of CYP19 and CYP11B2 (aldosterone synthase) is a promising treatment for breast cancer and the coinstantaneous cardiovascular diseases. By combination of important structural features of known CYP19 and CYP11B2 inhibitors, we succeeded in obtaining compounds 3 and 5 as selective dual inhibitors with IC(50) values around 50 and 20 nM toward CYP19 and CYP11B2, respectively. These compounds showed also good selectivity toward CYP11B1 (selectivity factors (IC(50 CYP11B1)/IC(50 CYP11B2)) around 50) and CYP17 (no inhibition).

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Available from: Qingzhong Hu, Feb 20, 2015
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    • "Due to the difficulty of identifying inhibitors of both human and rat CYP11B1 to facilitate the proof of concept in rats, compound IV was considered as a promising starting point for further modifications. However, as compound IV actually originated from a series of dual inhibitors of hCYP11B2 and hCYP19 [42] [43], it showed significant inhibition of hCYP19 as well (IC 50 ¼ 35 nM). Therefore, besides elevating the potencies against human and rat CYP11B1, improvement of the selectivity over both hCYP11B2 and hCYP19 is another challenge encountered. "
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    European Journal of Medicinal Chemistry 05/2015; 96. DOI:10.1016/j.ejmech.2015.04.013 · 3.45 Impact Factor
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    • "4.2.3. Selectivity tests versus hCYP17 and hCYP19 hCYP17 [22] and hCYP19 [53] enzyme preparations and assay procedures were performed as previously described. "
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    ABSTRACT: Aldosterone synthase (CYP11B2) is a promising therapeutic target for the treatment of cardiovascular diseases related to abnormally high aldosterone levels. On the basis of our previously identified lead compounds I-III, a series of 3-pyridinyl substituted aliphatic cycles were designed, synthesized and tested as CYP11B2 inhibitors. Aromaticity abolishment of the core was successfully applied to overcome the undesired CYP1A2 inhibition. This study resulted in a series of potent and selective CYP11B2 inhibitors, with compound 12 (IC(50) = 21 nM, SF = 50) as the most promising one, which shows no inhibition toward CYP1A2 at 2 µM. The design conception demonstrated in this study can be helpful in the optimization of CYP inhibitor drugs regarding CYP1A2 selectivity.
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