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. 2012;7(11):e48048.
doi: 10.1371/journal.pone.0048048. Epub 2012 Nov 1.

3-Pyridyl substituted aliphatic cycles as CYP11B2 inhibitors: aromaticity abolishment of the core significantly increased selectivity over CYP1A2

Lina Yin  1 , Qingzhong Hu, Rolf W Hartmann
Affiliations

3-Pyridyl substituted aliphatic cycles as CYP11B2 inhibitors: aromaticity abolishment of the core significantly increased selectivity over CYP1A2

Lina Yin et al. PLoS One. 2012.

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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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist. Although LY was employed by Elexopharm GmbH, this does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Structures of ACE inhibitor Enalapril, MR antagonists Spironolactone and Eplerenone, CYP11B2 inhibitor Fadrozole and aromatase inhibitor Exemestane.
Figure 2
Figure 2. Biological synthesis of aldosterone catalyzed by CYP11B2.
Figure 3
Figure 3. Conception of inhibitors design.
Figure 4
Figure 4. Reagents and conditions.
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.
Figure 5
Figure 5. Reagents and conditions.
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.
Figure 6
Figure 6. Reagents and conditions.
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.
Figure 7
Figure 7. Reagents and conditions.
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.
Figure 8
Figure 8. Structures of references I–III and compounds 1–21.
Figure 9
Figure 9. Binding of compound 4 into CYP11B2 homology model.
See this image and copyright information in PMC

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