title: Potent s-cis-locked bithiazole correctors of DeltaF508 cystic fibrosis transmembrane conductance regulator cellular processing for cystic fibrosis therapy.
abstract: N-(5-(2-(5-Chloro-2-methoxyphenylamino)thiazol-4-yl)-4-methylthiazol-2-yl)pivalamide 1 (compound 15Jf) was found previously to correct defective cellular processing of the cystic fibrosis protein DeltaF508-CFTR. Eight C4'-C5 C,C-bond-controlling bithiazole analogues of 1 were designed, synthesized, and evaluated to establish that constraining rotation about the bithiazole-tethering has a significant effect on corrector activity. For example, constraining the C4'-C5 bithiazole tether in the s-cis conformation [N-(2-(5-chloro-2-methoxyphenylamino)-7,8-dihydro-6 H-cyclohepta[1,2- d:3,4- d']bithiazole-2'-yl)pivalamide, 29] results in improved corrector activity. Heteroatom placement in the bithaizole core is also critical as evidenced by the decisive loss of corrector activity with s-cis constrained N-(2-(5-chloro-2-methoxyphenylamino)-5,6-dihydro-4 H-cyclohepta[1,2- d:3,4- d']bithiazole-2'-yl)pivalamide 33. In addition, computational models were utilized to examine the conformational preferences for select model systems. Following our analysis, the " s-cis-locked" cycloheptathiazolothiazole 29 was found to be the most potent bithiazole corrector, with an IC50 of approximately 450 nM.
authors.affiliation: Department of Chemistry, University of Californias Davis, Davis, California 95616, USA.
authors.forename: Gui Jun
authors.initials: GJ
authors.lastname: Yu
authors.forename: Choong L
authors.initials: CL
authors.lastname: Yoo
authors.forename: Baoxue
authors.initials: B
authors.lastname: Yang
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lodewyk
authors.forename: Liping
authors.initials: L
authors.lastname: Meng
authors.forename: Tamer T
authors.initials: TT
authors.lastname: El-Idreesy
authors.forename: James C
authors.initials: JC
authors.lastname: Fettinger
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Tantillo
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* / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects* / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D008956:Models, Chemical; D015394:Molecular Structure; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D013237:Stereoisomerism; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D013844:Thiazoles; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
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