High-Potency Phenylquinoxalinone Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Activators

Jung Ho Son, Jie S. Zhu, Puay Wah Phuan, Onur Cil, Andrew P. Teuthorn, Colton K. Ku, Sujin Lee, Alan S. Verkman, Mark J. Kurth

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


We previously identified phenylquinoxalinone CFTRact-J027 (4) as a cystic fibrosis transmembrane conductance regulator (CFTR) activator with an EC50 of ∼200 nM and demonstrated its therapeutic efficacy in mouse models of constipation. Here, structure-activity studies were done on 36 synthesized phenylquinoxalinone analogs to identify compounds with improved potency and altered metabolic stability. Synthesis of the phenylquinoxalinone core was generally accomplished by condensation of 1,2-phenylenediamines with substituted phenyloxoacetates. Structure-activity studies established, among other features, the privileged nature of a properly positioned nitro moiety on the 3-aryl group. Synthesized analogs showed improved CFTR activation potency compared to 4 with EC50 down to 21 nM and with greater metabolic stability. CFTR activators have potential therapeutic indications in constipation, dry eye, cholestatic liver diseases, and inflammatory lung disorders.

Original languageEnglish (US)
Pages (from-to)2401-2410
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number6
StatePublished - Mar 23 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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