Potent s-cis-Locked Bithiazole Correctors of ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator Cellular Processing for Cystic Fibrosis Therapy

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• 作者：Gui Jun Yu ; Choong L. Yoo ; Baoxue Yang ; Michael W. Lodewyk ; Liping Meng ; Tamer T. El-Idreesy ; James C. Fettinger ; Dean J. Tantillo ; A. S. Verkman ; Mark J. Kurth
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：October 9, 2008
• 年：2008
• 卷：51
• 期：19
• 页码：6044-6054
• 全文大小：481K
• 年卷期：v.51,no.19(October 9, 2008)
• ISSN：1520-4804

文摘

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 IC<sub>50sub> of ∼450 nM.