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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 t_1/2 ~ 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, (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 enant ...[more]

PMID: 23814642

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