The mineralocorticoid aldosterone is an important mediator of blood pressure, volume and electrolyte balance. However, excess aldosterone can be deleterious as a driver of vascular remodeling and tissue fibrosis associated with cardiometabolic diseases. Aldosterone synthase (AS) inhibitors (ASI) attenuate the production of aldosterone directly and have been proposed as an alternative to mineralocorticoid receptor (MR) antagonists (MRA) for blocking the pathological effects of excess aldosterone. Discovery of selective ASIs has been challenging because of the high sequence identity (93%) AS shares with cortisol synthase (CS), and the low identity of rodent AS compared to human (63%). Using cynomolgus (cyno) monkey-based models we identified BI 689648, a novel, highly selective ASI that exhibits an in vitro IC50 of 2 nM against AS and 300 nm against CS (150-fold selectivity) compared with the recently described ASIs FAD286 (3 nM AS; 90 nM CS; 40-fold) and LCI699 (10 nM AS; 80 nM CS; 8-fold). Following oral administration in cynos, BI 689648 (5 mg/kg) exhibits a peak plasma concentration of ~ 500 nM. For in vivo profiling we used an ACTH-challenge model in which BI 689648 was >20-fold more selective compared with FAD286 and LCI699. Since both FAD286 and LCI699 failed to provide adequate selectivity for CS when tested in patients, the desire for more selective molecules to test the ASI hypothesis remains high. Therefore, highly selective aldosterone synthase inhibitors such as BI 689648 represent an important step forward towards developing ASIs with greater potential for clinical success in cardiometabolic diseases.
Authors: Steven M. Weldon, Matthew A. Cerny, Kristina Gueneva-Boucheva, Derek Cogan, Xin Guo, Neil Moss, Jean-Hugues Parmentier, Jeremy Richman, Glenn A. Reinhart, Nicholas F. Brown
Keywords: aldosterone synthase inhibitor
DOI Number: 10.1124/jpet.116.236463 Publication Year: 2016
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