Potent s-cis-Locked Bithiazole Correctors of DF508 Cystic Fibrosis Transmembrane Conductance Regulator Cellular Processing for Cystic Fibrosis Therapy.
作者
Yu, Gui Jun;Yoo, Choong L.;Yang, Baoxue;Lodewyk, Michael W.;Meng, Liping;El-Idreesy, Tamer T.;Fettinger, James C.;Tantillo, Dean J.;Verkman, A. S.;Kurth, Mark J.;
[摘要]：N-(5-(2-(5-Chloro-2-methoxyphenylamino)thiazol-4-yl)-4-methylthiazol-2 -yl)pivalamide I (R1 = Me; R2 = H; R3 = 5-Cl-2-MeOC6H3) was found previously to correct defective cellular processing of the cystic fibrosis protein DF508-CFTR. Eight C4'-C5 C,C-bond-controlling bithiazole analogs of this compd. 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 of I [R1R2 = (CH2)3; (II)] results in improved corrector activity. Heteroatom placement in the bithiazole core is also crit. 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. In addn., computational models were utilized to examine the conformational preferences for select model systems. The "s-cis-locked" cycloheptathiazolothiazole II was found to be the most potent bithiazole corrector, with an IC50 of ~450 nM.
