Potent s-cis-locked bithiazole correctors of DeltaF508 cystic fibrosis transmembrane conductance regulator cellular processing for cystic fibrosis therapy.
Yu GJ, Yoo CL, Yang B, Lodewyk MW, Meng L, El-Idreesy TT, Fettinger JC, Tantillo DJ, Verkman AS, Kurth MJ.
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.