1. Academic Validation
  2. ABSOLUTE CONFIGURATION AND BIOLOGICAL PROPERTIES OF ENANTIOMERS OF CFTR INHIBITOR BPO-27

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

  • ACS Med Chem Lett. 2013 May 9;4(5):456-459. doi: 10.1021/ml400069k.
David S Snyder 1 Lukmanee Tradtrantip Sailaja Battula Chenjuan Yao Puay-Wah Phuan James C Fettinger Mark J Kurth A S Verkman
Affiliations

Affiliation

  • 1 Departments of Medicine and Physiology, University of California, San Francisco, CA, 94143-0521 ; Department of Chemistry, University of California, Davis, CA, 95616.
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.

Keywords

crystallography; cystic fibrosis; polycystic kidney disease; secretory diarrhea.

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