3-pyridyl substituted aliphatic cycles as cyp11b2 inhibitors aromaticity abolishment of the core significantly increased selectivity over cyp1a23-pyridyl代替脂肪族周期作为cyp11b2抑制剂芳香性废止的核心cyp1a2显著增加选择性.pdfVIP

3-Pyridyl Substituted Aliphatic Cycles as CYP11B2 Inhibitors: Aromaticity Abolishment of the Core Significantly Increased Selectivity over CYP1A2 1,2 1 1 Lina Yin , Qingzhong Hu *, Rolf W. Hartmann * ¨ 1 Pharmaceutical and Medicinal Chemistry, Saarland University Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarbrucken, Germany, 2 ElexoPharm ¨ GmbH, Saarbrucken, Germany 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 (IC50 = 21 nM, SF = 50) as the most promising one, which shows no inhibition toward CYP1A2 at 2 mM. The design conception demonstrated in this study can be helpful in the optimization of CYP inhibitor drugs regarding CYP1A2 selectivity. Citation: Yin L, Hu Q, Hartmann RW (2012) 3-Pyridyl Substituted Aliphatic Cycles as CYP11B2 Inhibitors: Aromaticity Abolishment of the Core Significantly Increased Selectivity over CYP1A2. PLoS ONE 7(11): e48048. doi:10.1371/journal.pone.0048048 Editor: Luis Eduardo M. Quintas, Universidade Federal do Rio de Janeiro, Brazil Received April 17, 2012; Accepted September 20, 2012; Published November 1, 2012 Copyright: 2012 Yin et al. This is an open-access article distri