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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    • "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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    • "The coordination of the sp 2 hybrid N to the heme iron was initially demonstrated between some antifungal agents and CYP enzymes, characterized by the red shift in ultraviolet absorp- tion[63], and subsequently between CYP19 inhibitors and their target enzyme[64]. The finding was soon successfully exploited in designing inhibitors of CYP19656667686970, CYP11B1717273, and CYP11B274757677787980818283. Many CYP17 inhibitors have also been designed with different sp 2 hybrid nitrogen-containing heterocycles substituted at the 17 position of modified pregnenolone or progesterone scaffolds in which a Δ16-17 double bond was commonly inserted. "
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