Selective dual inhibitors of CYP19 and CYP11B2: targeting cardiovascular diseases hiding in the shadow of breast cancer

J Med Chem. 2012 Aug 23;55(16):7080-9. doi: 10.1021/jm3004637. Epub 2012 Aug 3.

Abstract

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).

MeSH terms

  • Aromatase / metabolism*
  • Aromatase Inhibitors / chemical synthesis*
  • Aromatase Inhibitors / chemistry
  • Aromatase Inhibitors / pharmacology
  • Breast Neoplasms / complications*
  • Cardiovascular Diseases / complications
  • Cardiovascular Diseases / drug therapy*
  • Cytochrome P-450 CYP11B2 / antagonists & inhibitors*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 CYP3A Inhibitors
  • Female
  • Humans
  • In Vitro Techniques
  • Liver / enzymology
  • Quinolones / chemical synthesis*
  • Quinolones / chemistry
  • Quinolones / pharmacology
  • Solubility
  • Steroid 11-beta-Hydroxylase / antagonists & inhibitors
  • Steroid 17-alpha-Hydroxylase / antagonists & inhibitors
  • Structure-Activity Relationship

Substances

  • Aromatase Inhibitors
  • Cytochrome P-450 CYP3A Inhibitors
  • Quinolones
  • Aromatase
  • Cytochrome P-450 CYP3A
  • Steroid 17-alpha-Hydroxylase
  • CYP3A4 protein, human
  • Cytochrome P-450 CYP11B2
  • Steroid 11-beta-Hydroxylase