TY - JOUR
T1 - Potent s-cis-locked bithiazole correctors of ΔF508 cystic fibrosis transmembrane conductance regulator cellular processing for cystic fibrosis therapy
AU - Gui, Jun Yu
AU - Yoo, Choong L.
AU - Yang, Baoxue
AU - Lodewyk, Michael W.
AU - Meng, Liping
AU - El-Idreesy, Tamer T.
AU - Fettinger, James C.
AU - Tantillo, Dean J.
AU - Verkman, A. S.
AU - Kurth, Mark J.
PY - 2008/10/9
Y1 - 2008/10/9
N2 - 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.
AB - 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.
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U2 - 10.1021/jm800533c
DO - 10.1021/jm800533c
M3 - Article
C2 - 18788728
AN - SCOPUS:53549097399
VL - 51
SP - 6044
EP - 6054
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 19
ER -