Potent s-cis-locked bithiazole correctors of ΔF508 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 ΔF508-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-6H-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-4H-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 ∼450 nM.