BPO-27racemate是有效的CFTR抑制剂，IC50值为8nM。
BPO-27 racemate is a potent CFTR inhibitor with an IC50 of 8 nM.
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].
Following bolus interperitoneal administration in mice, serum (R)-1 decays with t1/2 ≈ 1.6 h and gives sustained therapeutic concentrations in kidney[1].
[1]. Snyder DS, et al. Absolute Configuration And Biological Properties of Enantiomers of CFTR Inhibitor BPO-27. ACS Med Chem Lett. 2013 May 9;4(5):456-459. [2]. Kim Y, et al. Benzopyrimido-pyrrolo-oxazine-dione (R)-BPO-27 Inhibits CFTR Chloride Channel Gating by Competition with ATP. Mol Pharmacol. 2015 Oct;88(4):689-96.
Cell experiment: | Whole-cell recordings are done on CFTR-expressing CHO-K1 cells. After establishing the whole-cell configuration, BPO-27 is added for 5 minutes, and then CFTR is activated by the addition of forskolin (10 μM) in the continued presence of BPO-27 (0.5 or 1 μM). Whole-cell currents are elicited by applying hyperpolarizing and depolarizing voltage pulses from a holding potential of 0 mV to potentials between +80 and ?80 mV in steps of 20 mV. Recordings are made at room temperature using an Axopatch-200B. Currents are digitized with a Digidata 1440A converter and filtered at 5 kHz[2]. |
Animal experiment: | Mice: (R)-BPO-27 is formulated at 1 mg/mL in 5% DMSO, 2.5% Tween-80 and 2.5% PEG400 in water. Male mice in a CD1 genetic background are administered 300 μL of the (R)-BPO-27 formulation by intraperitoneal injection. At specified times, blood samples are collected by eye bleed. At 4 h, kidneys are removed following renal arterial perfusion with PBS. Kidneys are weighed, mixed with acetic acid and homogenized for analysis[1]. |
参考文献: [1]. Snyder DS, et al. Absolute Configuration And Biological Properties of Enantiomers of CFTR Inhibitor BPO-27. ACS Med Chem Lett. 2013 May 9;4(5):456-459. | |
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