BPO-27 (racemate)

BPO-27 racemate is a potent CFTR inhibitor with an IC₅₀ of 8 nM. IC50 & Target: IC50: 8 nM^[1] In Vitro: The benzopyrimido-pyrrolo-oxazinedione BPO-27 is an analogue of PPQ-102, which inhibits CFTR with an IC₅₀ of 8 nM. The R enantiomer of BPO-27 inhibits CFTR chloride conductance with an IC₅₀ of 4 nM, while S enantiomer is inactive. In vitro metabolic stability in hepatic microsomes shows both enantiomers as stable, with less than 5% metabolism in 4 h^[1]. (R)-BPO-27 binds near the canonical ATP binding site. Whole-cell patch-clamp studies shows linear CFTR currents with a voltage-independent (R)-BPO-27 block mechanism. At a concentration of (R)-BPO-27 that inhibits CFTR chloride current by 50%, the EC₅₀ for ATP activation of CFTR increases from 0.27 to 1.77 mM^[2]. In Vivo: Following bolus interperitoneal administration in mice, serum (R)-1 decays with t_1/2 ≈ 1.6 h and gives sustained therapeutic concentrations in kidney^[1].