BI 689648 is a novel, highly selective aldosterone synthase inhibitor which can inhibit CYP11B1 and CYP11B2 with IC50s of 310 and 2.1 nM, respectively.
Compare with the FADs and LCI699, BI 689648 is highly selective in vitro, providing an IC50 for CYP11B2 of 2.1 nM and a selectivity factor of 149 over CYP11B1. FAD286, by comparison, shows a similar IC50 for CYP11B2 (2.5 nM); however, its greater potency against CYP11B1 (94 nM) results in a comparatively modest selectivity factor of 38, approximately 4-fold less than BI 689648[1].
After oral administration in cyno monkeys, BI 689648 (5 mg/kg) exhibits a peak plasma concentration of ~500 nM. For BI 689648 (aldosterone EC50=2 nM), appreciable changes in 11-DOC are only noted at plasma concentrations >2000 nM or >1000-fold its aldosterone EC50 while FAD286 shows a window of ~100-fold. BI 689648 exhibits minimal impact on 11-DC and only at very high plasma concentrations (~10 μM)[1].
[1]. Weldon SM, et al. Selectivity of BI 689648, a Novel, Highly Selective Aldosterone Synthase Inhibitor: Comparison with FAD286 and LCI699 in Nonhuman Primates. J Pharmacol Exp Ther. 2016 Oct;359(1):142-50.