title: Potentiation of ΔF508- and G551D-CFTR-Mediated Cl- Current by Novel Hydroxypyrazolines.
abstract: The most common mutation of CFTR, affecting approximately 90% of CF patients, is a deletion of phenylalanine at position 508 (F508del, ΔF508). Misfolding of ΔF508-CFTR impairs both its trafficking to the plasma membrane and its chloride channel activity. To identify small molecules that can restore channel activity of ΔF508-CFTR, we synthesized and evaluated eighteen novel hydroxypyrazoline analogues as CFTR potentiators. To elucidate potentiation activities of hydroxypyrazolines for ΔF508-CFTR, CFTR activity was measured using a halide-sensitive YFP assay, Ussing chamber assay and patch-clamp technique. Compounds 7p, 7q and 7r exhibited excellent potentiation with EC50 value <10 μM. Among the compounds, 7q (a novel CFTR potentiator, CP7q) showed the highest potentiation activity with EC50 values of 0.88 ± 0.11 and 4.45 ± 0.31 μM for wild-type and ΔF508-CFTR, respectively. In addition, CP7q significantly potentiated chloride conductance of G551D-CFTR, a CFTR gating mutant; its maximal potentiation activity was 1.9 fold higher than the well-known CFTR potentiator genistein. Combination treatment with CP7q and VX-809, a corrector of ΔF508-CFTR, significantly enhanced functional rescue of ΔF508-CFTR compared with VX-809 alone. CP7q did not alter the cytosolic cAMP level and showed no cytotoxicity at the concentration showing maximum efficacy. The hydroxypyrazolines may be potential development candidates for drug therapy of cystic fibrosis.
authors: College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 406-840, Korea.|Department of Integrated OMICS for Biomedical Science, WCU Program of Graduate School, Yonsei University, Seoul 120-749, Korea.
authors: Jinhong
authors: J
authors: Park
authors: Department of Chemistry, Kurukshetra University, Kurukshetra, Haryana 136119, India.
authors: Poonam
authors: P
authors: Khloya
authors: College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 406-840, Korea.|Department of Integrated OMICS for Biomedical Science, WCU Program of Graduate School, Yonsei University, Seoul 120-749, Korea.
authors: Yohan
authors: Y
authors: Seo
authors: Department of Chemistry, Kurukshetra University, Kurukshetra, Haryana 136119, India.
authors: Satish
authors: S
authors: Kumar
authors: Department of Integrated OMICS for Biomedical Science, WCU Program of Graduate School, Yonsei University, Seoul 120-749, Korea.
authors: Ho K
authors: HK
authors: Lee
authors: College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 406-840, Korea.
authors: Dong-Kyu
authors: DK
authors: Jeon
authors: College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 406-840, Korea.
authors: Sungwoo
authors: S
authors: Jo
authors: Department of Chemistry, Kurukshetra University, Kurukshetra, Haryana 136119, India.
authors: Pawan K
authors: PK
authors: Sharma
authors: College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 406-840, Korea.|Department of Integrated OMICS for Biomedical Science, WCU Program of Graduate School, Yonsei University, Seoul 120-749, Korea.
authors: Wan
authors: W
authors: Namkung
mesh_terms: D000631:Aminopyridines / Q000627:therapeutic use; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry; D052117:Benzodioxoles / Q000627:therapeutic use; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002712:Chlorides / Q000737:chemistry*; D000242:Cyclic AMP / Q000378:metabolism; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004847:Epithelial Cells / Q000166:cytology; D017353:Gene Deletion; D019833:Genistein / Q000737:chemistry; D006801:Humans; D008164:Luminescent Proteins / Q000737:chemistry; D009154:Mutation; D009666:Nose / Q000502:physiology; D018408:Patch-Clamp Techniques; D010649:Phenylalanine / Q000235:genetics; D011720:Pyrazoles / Q000627:therapeutic use*; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000627:therapeutic use; D000096926:Benzenesulfonamides
chemical_list: D000631:Aminopyridines; D001426:Bacterial Proteins; D052117:Benzodioxoles; D002712:Chlorides; D000242:Cyclic AMP; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D019833:Genistein; D008164:Luminescent Proteins; D010649:Phenylalanine; D011720:Pyrazoles; D013449:Sulfonamides; C000609214:4-(3-(2,4-dihydroxyphenyl)-5-(2,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C505032:CFTR protein, human; C093349:cystic fibrosis transmembrane conductance regulator delta F508; C054562:yellow fluorescent protein, Bacteria; C569105:lumacaftor