title: Pyrazolylthiazole as DeltaF508-cystic fibrosis transmembrane conductance regulator correctors with improved hydrophilicity compared to bithiazoles.
abstract: Deletion of phenylalanine residue 508 (DeltaF508) in the cystic fibrosis (CF) transmembrane conductance regulator protein (CFTR) is a major cause of CF. Small molecule "correctors" of defective DeltaF508-CFTR cellular processing hold promise for CF therapy. We previously identified and characterized bithiazole CF corrector 1 and s-cis-locked bithiazole 2. Herein, we report the regiodivergent synthesis of Ngamma and Nbeta isomers of thiazole-tethered pyrazoles with improved hydrophilicity compared to bithiazoles. We synthesized a focused library of 54 pyrazolylthiazoles 3, which included examples of both regioisomers 4 and 5. The thiazole-tethered pyrazoles allowed incorporation of property-modulating functionality on the pyrazole ring (ester, acid, and amide) while retaining DeltaF508-CFTR corrector activity (EC(50)) of under 1 microM. The most active pyrazolylthiazole (14h) has an experimentally determined log P of 4.1, which is 1.2 log units lower than bithiazole CF corrector 1.
authors.affiliation: Department of Chemistry, University of California, Davis, Davis, California 95616, USA.
authors.forename: Long
authors.initials: L
authors.lastname: Ye
authors.forename: John M
authors.initials: JM
authors.lastname: Knapp
authors.forename: Panjamaporn
authors.initials: P
authors.lastname: Sangwung
authors.forename: James C
authors.initials: JC
authors.lastname: Fettinger
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kurth
mesh_terms: D003550:Cystic Fibrosis / Q000188:drug therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects*; D016368:Frameshift Mutation; D006801:Humans; D011720:Pyrazoles / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D011720:Pyrazoles; D054852:Small Molecule Libraries; D013844:Thiazoles; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator