CFTR is a chloride channel, that controls ion and water secretion and absorption in epithelial tissues. CFTR protein dysfunction leads to abnormal ion transport across the airway epithelium[3]. PPQ2 as a small molecule CFTR inhibitor that completely inhibited CFRR chloride current with IC50 value of 90 nM[4]. In vitro, PPQ-102 at the dose of 10µM inhibited CFTR almost 100% in (nonpermeabilized) human intestinal (T84) and bronchial cells following maximal CFTR activation by forskolin and IBMX. However, PPQ-102 did not inhibit calcium-activated chloride channels or cellular cAMP production[4]. PPQ-102 also inhibited the volume-regulated anion channel (VRAC) conductance with IC50 value of 20μM in HEK293 cells[5]. Treatment of NCI-H292 cells with 10μM PPQ-102 induced a two-fold increase in VEGF-A synthesis[3]. In the presence of NADPH, PPQ-102 lost in hepatic microsomes about 60% within 30min. No loss of PPQ-102 was seen in the absence of NADPH. In vivo, PPQ-102 was undetectable in serum, kidney and urine at 30-60 min after intravenous administration of 300μg PPQ-102 by LC/MS assay with sensitivity better than 100nM[6].
作用机制
PPQ-102 inhibits CFTR by an altered channel gating mechanism, with stabilization of the channel closed state[4].
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