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

ABSTRACT: We previously identified phenylquinoxalinone CFTR_act-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

SUBMITTER: Son JH 

PROVIDER: S-EPMC5463557 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature