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Updated: Jul 2, 2026

Functional Reconstitution and Channel Activity Measurements of Purified Wildtype and Mutant CFTR Protein
Published on: March 9, 2015
Thiazolidinone CFTR inhibitors with improved water solubility identified by structure-activity analysis
1Departments of Medicine and Physiology, Cardiovascular Research Institute, University of California, 1246 Health Sciences East Tower, San Francisco, CA 94143-0521, USA. Nitin.Sonawane@ucsf.edu
Abstract:
The thiazolidinone 3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl)methylene]-2-thioxo-4-thiazolidinone (CFTR(inh)-172) inhibits cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel conductance with submicromolar affinity and blocks cholera toxin-induced intestinal fluid secretion. Fifty-eight CFTR(inh)-172 analogs were synthesized to identify CFTR inhibitors with improved water solubility, exploring modifications in its two phenyl rings, thiazolidinone core, and core-phenyl connectors. Greatest CFTR inhibition potency was found for 3-CF(3) and polar group-substituted-phenyl rings, and a thiazolidinone core. Two compounds with approximately 1muM CFTR inhibition potency and solubility >180 microM (>10-fold more than CFTR(inh)-172) were identified: Tetrazolo-172, containing 4-tetrazolophenyl in place of 4-carboxyphenyl, and Oxo-172, containing thiazolidinedione in place of the thiazolidinone core. These water soluble thiazolidinone analogs had low cellular toxicity. The improved water solubility of Tetrazolo- and Oxo-172 make them potential lead candidates for therapy of secretory diarrheas and polycystic kidney disease.
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