title: 3-Pyridyl substituted aliphatic cycles as CYP11B2 inhibitors: aromaticity abolishment of the core significantly increased selectivity over CYP1A2.
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.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarbrücken, Germany.
authors.forename: Lina
authors.initials: L
authors.lastname: Yin
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Hu
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000465:Algorithms; D000730:Androstadienes / Q000494:pharmacology; D047072:Aromatase Inhibitors / Q000494:pharmacology; D020134:Catalytic Domain; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D015195:Drug Design; D004656:Enalapril / Q000494:pharmacology; D000077545:Eplerenone; D017316:Fadrozole / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013696:Temperature
chemical_list: D000730:Androstadienes; D047072:Aromatase Inhibitors; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D013148:Spironolactone; D000077545:Eplerenone; D004656:Enalapril; D019405:Cytochrome P-450 CYP11B2; D017316:Fadrozole; C056516:exemestane