Absolute configuration and biological properties of enantiomers of CFTR inhibitor BPO-27

David S. Snyder, Lukmanee Tradtrantip, Sailaja Battula, Chenjuan Yao, Puay Wah Phuan, James C. Fettinger, Mark J. Kurth, A. S. Verkman

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)456-459
Number of pages4
JournalACS Medicinal Chemistry Letters
Volume4
Issue number5
DOIs
StatePublished - May 9 2013

Keywords

  • crystallography
  • Cystic fibrosis
  • polycystic kidney disease
  • secretory diarrhea

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

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    Snyder, D. S., Tradtrantip, L., Battula, S., Yao, C., Phuan, P. W., Fettinger, J. C., Kurth, M. J., & Verkman, A. S. (2013). Absolute configuration and biological properties of enantiomers of CFTR inhibitor BPO-27. ACS Medicinal Chemistry Letters, 4(5), 456-459. https://doi.org/10.1021/ml400069k