Absolute Configuration and Biological Properties of Enantiomers of CFTR Inhibitor BPO-27

详细信息    查看全文

• 作者：David S. Snyder ; Lukmanee Tradtrantip ; Sailaja Battula ; Chenjuan Yao ; Puay-wah Phuan ; James C. Fettinger ; Mark J. Kurth ; A. S. Verkman
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：May 9, 2013
• 年：2013
• 卷：4
• 期：5
• 页码：456-459
• 全文大小：273K
• 年卷期：v.4,no.5(May 9, 2013)
• ISSN：1948-5875

文摘

We previously reported benzopyrimido-pyrrolo-oxazinedione (BPO) inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and showed their efficacy in a model of polycystic kidney disease. Here, we separated the enantiomers of lead compound BPO-27 (1), which contains a single chiral center, and determined their absolute configuration, activity, and metabolic stability. Following separation by chiral supercritical fluid chromatography, the R enantiomer, as determined by X-ray crystallography, inhibited CFTR chloride conductance with IC₅₀ 鈮?4 nM, while S enantiomer was inactive. In vitro metabolic stability in hepatic microsomes showed both enantiomers as stable, with <5% metabolism in 4 h. Following bolus interperitoneal administration in mice, serum (R)-1 decayed with t_1/2 鈮?1.6 h and gave sustained therapeutic concentrations in kidney.

Keywords:

Cystic fibrosis; polycystic kidney disease; secretory diarrhea; crystallography