BI 689648

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. IC50 & Target: IC50: 310 nM (CYP11B1), 2.1 nM (CYP11B2)^[1] In Vitro: 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]. In Vivo: 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].