AI Article Synopsis
- Researchers identified a new class of CFTR inhibitors called pyrimido-pyrrolo-quinoxalinediones (PPQs) that may help slow cyst enlargement in polycystic kidney disease and manage intestinal fluid loss in diarrheal conditions.
- The most effective compound, PPQ-102, shows significant inhibition of CFTR chloride currents at low concentrations (IC(50) ≈ 90 nM) and has unique properties that prevent it from being affected by cellular membrane potential.
- In experimental models, PPQ-102 not only inhibited CFTR activity but also effectively reduced cyst size and prevented further expansion in kidney organ culture, making it the strongest CFTR inhibitor found so far.
Article Abstract
Inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel are predicted to slow cyst enlargement in polycystic kidney disease and reduce intestinal fluid loss in secretory diarrheas. Screening of approximately 110000 small synthetic and natural compounds for inhibition of halide influx in CFTR-expressing epithelial cells yielded a new class of pyrimido-pyrrolo-quinoxalinedione (PPQ) CFTR inhibitors. Testing of 347 analogues established structure-activity relationships. The most potent compound, 7,9-dimethyl-11-phenyl-6-(5-methylfuran-2-yl)-5,6-dihydro-pyrimido[4',5'-3,4]pyrrolo[1,2-a]quinoxaline-8,10-(7H,9H)-dione, PPQ-102, completely inhibited CFTR chloride current with IC(50) approximately 90 nM. The PPQs, unlike prior CFTR inhibitors, are uncharged at physiological pH, and therefore not subject to membrane potential-dependent cellular partitioning or block efficiency. Patch-clamp analysis confirmed voltage-independent CFTR inhibition by PPQ-102 and showed stabilization of the channel closed state. PPQ-102 prevented cyst expansion and reduced the size of preformed cysts in a neonatal kidney organ culture model of polycystic kidney disease. PPQ-102 is the most potent CFTR inhibitor identified to date.
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|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319430 | PMC |
| http://dx.doi.org/10.1021/jm9009873 | DOI Listing |
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