4'-Methyl-4,5'-bithiazole-based correctors of defective delta F508-CFTR cellular processing.
The synthesis and Delta F508-CFTR corrector activity of a 148-member methylbithiazole-based library are reported. Synthetic routes were devised and optimized to generate methylbithiazole analogs in four steps. Corrector potency and efficacy were assayed using epithelial cells expressing human Delta F508-CFTR. These structure-activity data establish that the bithiazole substructure plays a critical function; eight novel methylbithiazole correctors were identified with low micromolar potencies.
Yoo
Choong Leol
CL
Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, USA.
Yu
Gui Jun
GJ
Yang
Baoxue
B
Robins
Lori I
LI
Verkman
A S
AS
Kurth
Mark J
MJ
D000586:Amination; D002460:Cell Line; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D013844:Thiazoles; D019005:Cystic Fibrosis Transmembrane Conductance Regulator