(R)-BPO-27 is an orally active and potent ATP-competitive CFTR inhibitor (IC50: 4 nM) for the study of diarrhoea and polycystic kidney.

In HEK-293T cells, (R)-BPO-27 exhibits a dose-response inhibition and inhibits the CFTR current by 50% at 0.53 nM. Acting from the cytoplasmic side, (R)-BPO-27 has low membrane permeability[3].In a single-channel patch-clamp experiment with HEK-293T cells expressing human wild-type CFTR, (R)-BPO-27 reduces the channel open probability (NPo) from 0.29 to 0.08. It modestly reduces the mean channel open time and strongly increases the mean channel closed time. In contrast, (S)-BPO-27 does not affect any of these parameters[3].(R)-BPO-27 is directly applied to the cytoplasmic membrane surface and stabilizes the CFTR channel closed state with an IC50 of 600 pM in a single-channel electrophysiology assay[2].In CFTR-expressing FRT cells after CFTR stimulation by cAMP agonist, (R)-BPO-27 (10 μM, 10 min pretreatment) inhibits Cl- current with apparent IC50 values of 5 and 10 nM for CPT-cAMP and 8-Br-cGMP, respectively. It also shows an IC50 of 4 nM for inhibition of forskolin-stimulated CFTR Cl- current in FRT cells[1].

In a PK study, (R)-BPO-27 (intraperitoneal administration; 10 mg/kg) decays with a t1/2≈1.6 h and provides sustained therapeutic concentrations in the kidney[3].
Preventing fluid accumulation in closed midjejunal loops produced by cholera toxin, (R)-BPO-27 (intraperitoneal injection; 5 mg/kg; 30 min before abdominal surgery) yields an intestinal loop weight/length ratio similar to that in PBS-injected loops. This effect is dose-dependent, with an IC50 value of 0.1 mg/kg[1].
Administered via intraperitoneal injection or oral administration at 5 mg/kg, (R)-BPO-27 demonstrates slow metabolism and maintains sustained serum levels for at least 4 hours. Oral bioavailability of (R)-BPO-27 in mouse pharmacokinetics and toxicity study is approximately 94% based on AUC analysis[1].