title: Constrained bithiazoles: small molecule correctors of defective ΔF508-CFTR protein trafficking.
abstract: Conformationally constrained bithiazoles were previously found to have improved efficacy over nonconstrained bithiazoles for correction of defective cellular processing of the ΔF508 mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein. In this study, two sets of constrained bithiazoles were designed, synthesized, and tested in vitro using ΔF508-CFTR expressing epithelial cells. The SAR data demonstrated that modulating the constraining ring size between 7- versus 8-membered in these constrained bithiazole correctors did not significantly enhance their potency (IC50), but strongly affected maximum efficacy (Vmax), with constrained bithiazoles 9e and 10c increasing Vmax by 1.5-fold compared to benchmark bithiazole corr4a. The data suggest that the 7- and 8-membered constrained ring bithiazoles are similar in their ability to accommodate the requisite geometric constraints during protein binding.
authors: Department of Chemistry, University of California , One Shields Avenue, Davis, California 95616, United States.
authors: Keith C
authors: KC
authors: Coffman
authors: Huy H
authors: HH
authors: Nguyen
authors: Puay-Wah
authors: PW
authors: Phuan
authors: Brandi M
authors: BM
authors: Hudson
authors: Gui J
authors: GJ
authors: Yu
authors: Alex L
authors: AL
authors: Bagdasarian
authors: Deanna
authors: D
authors: Montgomery
authors: Michael W
authors: MW
authors: Lodewyk
authors: Baoxue
authors: B
authors: Yang
authors: Choong L
authors: CL
authors: Yoo
authors: A S
authors: AS
authors: Verkman
authors: Dean J
authors: DJ
authors: Tantillo
authors: Mark J
authors: MJ
authors: Kurth
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003508:Cycloheptanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D034242:Cyclooctanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009154:Mutation; D021381:Protein Transport; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013961:Thyroid Gland / Q000166:cytology
chemical_list: D003508:Cycloheptanes; D034242:Cyclooctanes; C000595003:N-(9-((5-chloro-2-methoxyphenyl)amino)-4,5,6,7-tetrahydrocycloocta(1,2-d-3,4-d')bis(thiazole)-2-yl)isobutyramide; D013844:Thiazoles; C000595002:methyl 4-((8-((5-chloro-2-methoxyphenyl)amino)-5,6-dihydro-4H-cyclohepta(1,2-d-3,4-d')bis(thiazole)-2-yl)amino)-4-oxobutanoate; D019005:Cystic Fibrosis Transmembrane Conductance Regulator