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ABSOLUTE CONFIGURATION AND BIOLOGICAL PROPERTIES OF ENANTIOMERS OF CFTR INHIBITOR BPO-27.


ABSTRACT: 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 ~ 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 t1/2 ~ 1.6 h and gave sustained therapeutic concentrations in kidney.

SUBMITTER: Snyder DS 

PROVIDER: S-EPMC3694630 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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ABSOLUTE CONFIGURATION AND BIOLOGICAL PROPERTIES OF ENANTIOMERS OF CFTR INHIBITOR BPO-27.

Snyder David S DS   Tradtrantip Lukmanee L   Battula Sailaja S   Yao Chenjuan C   Phuan Puay-Wah PW   Fettinger James C JC   Kurth Mark J MJ   Verkman A S AS  

ACS medicinal chemistry letters 20130501 5


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, (<b>1</b>), which contains a single chiral center, and determined their absolute configuration, activity and metabolic stability. Following separation by chiral supercritical fluid chromatography, the <i>R</i> enant  ...[more]

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