Constrained Bithiazoles: Small Molecule Correctors of Defective 螖F508鈥揅FTR Protein Trafficking

详细信息    查看全文

• 作者：Keith C. Coffman ; Huy H. Nguyen ; Puay-Wah Phuan ; Brandi M. Hudson ; Gui J. Yu ; Alex L. Bagdasarian ; Deanna Montgomery ; Michael W. Lodewyk ; Baoxue Yang ; Choong L. Yoo ; A. S. Verkman ; Dean J. Tantillo ; Mark J. Kurth
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：August 14, 2014
• 年：2014
• 卷：57
• 期：15
• 页码：6729-6738
• 全文大小：500K
• ISSN：1520-4804

文摘

Conformationally constrained bithiazoles were previously found to have improved efficacy over nonconstrained bithiazoles for correction of defective cellular processing of the 螖F508 mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein. In this study, two sets of constrained bithiazoles were designed, synthesized, and tested in vitro using 螖F508鈥揅FTR expressing epithelial cells. The SAR data demonstrated that modulating the constraining ring size between 7- versus 8-membered in these constrained bithiazole correctors did not significantly enhance their potency (IC₅₀), but strongly affected maximum efficacy (V_max), with constrained bithiazoles 9e and 10c increasing V_max by 1.5-fold compared to benchmark bithiazole corr4a. The data suggest that the 7- and 8-membered constrained ring bithiazoles are similar in their ability to accommodate the requisite geometric constraints during protein binding.