title: Thiazolidinone CFTR inhibitors with improved water solubility identified by structure-activity analysis.
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.
authors.affiliation: Departments 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
authors.forename: N D
authors.initials: ND
authors.lastname: Sonawane
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D015394:Molecular Structure; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014867:Water / Q000737:chemistry*
chemical_list: D045162:Thiazolidinediones; D014867:Water; D019005:Cystic Fibrosis Transmembrane Conductance Regulator