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
  • 1. Departments of Medicine and Physiology, University of California, San Francisco, CA, 94143-0521 ; Department of Chemistry, University of California, Davis, CA, 95616.
PMID: 23814642 DOI: 10.1021/ml400069k
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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