Potent s-cis-locked bithiazole correctors of DeltaF508 cystic fibrosis transmembrane conductance regulator cellular processing for cystic fibrosis therapy.
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.
Yu
Gui Jun
GJ
Department of Chemistry, University of Californias Davis, Davis, California 95616, USA.
Yoo
Choong L
CL
Yang
Baoxue
B
Lodewyk
Michael W
MW
Meng
Liping
L
El-Idreesy
Tamer T
TT
Fettinger
James C
JC
Tantillo
Dean J
DJ
Verkman
A S
AS
Kurth
Mark J
MJ
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*
D013844:Thiazoles; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
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