Novel Pyridyl- or Isoquinolinyl-Substituted Indolines and Indoles as Potent and Selective Aldosterone Synthase Inhibitors
2014-06-26T00:00:00Z (GMT) by
Pathologically, high levels of aldosterone are associated with severe cardiovascular diseases such as congestive heart failure, hypertension, and myocardial fibrosis. The inhibition of aldosterone synthase (CYP11B2) to reduce aldosterone levels has been proposed as a promising treatment for diseases related to CYP11B2 because it is the crucial enzyme in the biosynthesis of aldosterone. A series of novel pyridyl- or isoquinolinyl-substituted indolines and indoles was designed via a ligand-based approach. The synthesized compounds were tested and found to be strong CYP11B2 inhibitors. The most potent ones showed IC<sub>50</sub> values of less than 3 nM, being similarly potent as fadrozole and LCI699. Among them, compounds <b>14</b> and <b>23</b> showed good selectivity over the highly homologous CYP11B1, with selectivity factors (SF = IC<sub>50 CYP11B1</sub>/IC<sub>50 CYP11B2</sub>) around 170; thus, they are superior to fadrozole and LCI699 (SFs < 15). These potent CYP11B2 inhibitors exhibited no inhibition (IC<sub>50</sub> > 50 μM) of a panel of hepatic CYP enzymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 and the crucial steroidogenic enzymes, CYP17 and CYP19. Because of these advantageous profiles, compounds <b>14</b> and <b>23</b> are considered to be candidates for further in vivo evaluation.