Tetrahydropyrroloquinolinone Type Dual Inhibitors of Aromatase/Aldosterone Synthase as a Novel Strategy for Breast Cancer Patients with Elevated Cardiovascular Risks

The application of aromatase inhibitors to postmenopausal breast cancer patients increases the risk of cardiovascular diseases (CVD), which is believed to be caused by the abnormally high concentrations of aldosterone as a consequence of the estrogen deficiency. Dual inhibitors of aromatase (CYP19) and aldosterone synthase (CYP11B2) are therefore proposed as a novel strategy for the adjuvant therapy to reduce the CVD risk for these patients. By combining decisive structural features of CYP11B2 and CYP19 inhibitors into a common template, a series of pyridinylmethyl substituted 1,2,5,6-tetrahydro-pyrrolo­[3,2,1-<i>ij</i>]­quinolin-4-ones were designed and synthesized. Interestingly, the substituents on the methylene bridge showed strong influences on the inhibitory activities leading to opposite effects, that is, a given substituent showed an increase in inhibition of one enzyme, while it led to a decrease for the other enzyme. The compromise of this conflict led to compounds <b>3j</b>, <b>3k</b>, <b>3n</b>, and <b>3p</b> as potent and selective dual inhibitors of CYP19 and CYP11B2, especially compound <b>3p</b>, which exhibited IC₅₀ values of 32 and 41 nM for CYP19 and CYP11B2, respectively, and a high selectivity toward CYP17 and CYP11B1. This compound is considered as a candidate for further evaluation in vivo

Structures of ACE inhibitor Enalapril, MR antagonists Spironolactone and Eplerenone, CYP11B2 inhibitor Fadrozole and aromatase inhibitor Exemestane.

<p>Structures of ACE inhibitor Enalapril, MR antagonists Spironolactone and Eplerenone, CYP11B2 inhibitor Fadrozole and aromatase inhibitor Exemestane.</p

Reagents and conditions.

<p>a) Method A: Tf₂O, CH₂Cl₂, 2,6-di-tert-butyl-4-methylpyridine, 2 h; b) Method B: Pd(PPh₃)₄, pyridine-3-boronic acid, Na₂CO₃, DME, H₂O, 90°C, 2 h; c) Method C: 5% Pd/C, MeOH, H₂, RT, 2 d.</p

Inhibition of human hepatic enzyme CYP1A2 by selected compounds.

[a]<p>Recombinantly expressed enzyme from baculovirus infected insect microsomes (Supersomes); furafylline: IC₅₀ = 2420 nM.</p

Reagents and conditions.

<p>a) Method A: Tf₂O, CH₂Cl₂, 2,6-di-tert-butyl-4-methylpyridine, 2 h; b) Method B: Pd(PPh₃)₄, pyridine-3-boronic acid, Na₂CO₃, DME, H₂O, 90°C, 2 h; c) Method C: 5% Pd/C, MeOH, H₂, RT, 2 d. d) Method D: NaBH₄, MeOH, RT, 2 h; e) CH₃PPh₃Br, n-BuLi, THF, 30 min at −78°C, 2 h at RT, f) BH₃-THF, 3M NaOH, 35% H₂O₂, THF, g) PCC, CH2Cl2, reflux 2 d.</p

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

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 <b>3</b> and <b>5</b> as selective dual inhibitors with IC₅₀ 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)

Reagents and conditions.

<p>a) Method A: Tf₂O, CH₂Cl₂, 2,6-di-tert-butyl-4-methylpyridine, 2 h; b) Method B: Pd(PPh₃)₄, pyridine-3-boronic acid, Na₂CO₃, DME, H₂O, 90°C, 2 h.</p

Optimization of Hydroxybenzothiazoles as Novel Potent and Selective Inhibitors of 17β-HSD1

17β-HSD1 is a novel target for the treatment of estrogen-dependent diseases, as it catalyzes intracellular estradiol formation. Starting from two recently described compounds, highly active and selective inhibitors were developed. Benzoyl <b>6</b> and benzamide <b>17</b> are the most selective compounds toward 17β-HSD2 described so far. They also showed a promising profile regarding activity in T47-D cells, selectivity toward ERα and ERβ, inhibition of hepatic CYP enzymes, metabolic stability, and inhibition of marmoset 17β-HSD1 and 17β-HSD2

Binding of compound 4 into CYP11B2 homology model.

<p>Binding of compound 4 into CYP11B2 homology model.</p

Inhibition of human CYP11B1 and CYP11B2 by references <b>I</b>–<b>III</b> and compounds <b>1</b>–<b>21</b>.

[a]<p>Hamster fibroblasts expressing human CYP11B1 or CYP11B2, respectively; substrate: deoxycorticosterone, 100 nM.</p>[b]<p>SF: selectivity factor = IC_{50 CYP11B1}/IC_{50 CYP11B2}.</p>[c]<p>Fad: fadrozole; nd: not determined.</p