Phenylquinoxalinone CFTR activator as potential prosecretory therapy for constipation

Onur Cil, Puay-Wah Phuan, Jung-Ho Son, Jie S Zhu, Colton K Ku, Niloufar Akhavan Tabib, Andrew P Teuthorn, Loretta Ferrera, Nicholas C Zachos, Ruxian Lin, Luis J V Galietta, Mark Donowitz, Mark J Kurth, Alan S Verkman

Research output: Contribution to journalArticlepeer-review


Constipation is a common condition for which current treatments can have limited efficacy. By high-throughput screening, we recently identified a phenylquinoxalinone activator of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel that stimulated intestinal fluid secretion and normalized stool output in a mouse model of opioid-induced constipation. Here, we report phenylquinoxalinone structure-activity analysis, mechanism of action, animal efficacy data in acute and chronic models of constipation, and functional data in ex vivo primary cultured human enterocytes. Structure-activity analysis was done on 175 phenylquinoxalinone analogs, including 15 synthesized compounds. The most potent compound, CFTRact-J027, activated CFTR with EC50 ∼ 200 nM, with patch-clamp analysis showing a linear CFTR current-voltage relationship with direct CFTR activation. CFTRact-J027 corrected reduced stool output and hydration in a mouse model of acute constipation produced by scopolamine and in a chronically constipated mouse strain (C3H/HeJ). Direct comparison with the approved prosecretory drugs lubiprostone and linaclotide showed substantially greater intestinal fluid secretion with CFTRact-J027, as well as greater efficacy in a constipation model. As evidence to support efficacy in human constipation, CFTRact-J027 increased transepithelial fluid transport in enteroids generated from normal human small intestine. Also, CFTRact-J027 was rapidly metabolized in vitro in human hepatic microsomes, suggesting minimal systemic exposure upon oral administration. These data establish structure-activity and mechanistic data for phenylquinoxalinone CFTR activators, and support their potential efficacy in human constipation.

Original languageEnglish
Pages (from-to)14-26.e4
JournalTranslational Research
Publication statusPublished - Apr 2017


  • Acute Disease
  • Animals
  • Body Fluids
  • Cell Line
  • Chronic Disease
  • Constipation
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Disease Models, Animal
  • Duodenum
  • Female
  • Gastric Acid
  • Humans
  • Jejunum
  • Lubiprostone
  • Mice
  • Microsomes, Liver
  • Patch-Clamp Techniques
  • Peptides
  • Quinoxalines
  • Rats
  • Scopolamine Hydrobromide
  • Structure-Activity Relationship
  • Journal Article


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