title: High-Potency Phenylquinoxalinone Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Activators.
abstract: We previously identified phenylquinoxalinone CFTRact-J027 (4) as a cystic fibrosis transmembrane conductance regulator (CFTR) activator with an EC50of ∼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 EC50down 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.
authors.affiliation: Department of Chemistry, University of California , Davis, California 95616, United States.
authors.forename: Jung-Ho
authors.initials: JH
authors.lastname: Son
authors.affiliation: Department of Chemistry, University of California , Davis, California 95616, United States.
authors.forename: Jie S
authors.initials: JS
authors.lastname: Zhu
authors.affiliation: Departments of Medicine & Physiology, University of California , San Francisco, California 94143, United States.
authors.forename: Puay-Wah
authors.initials: PW
authors.lastname: Phuan
authors.affiliation: Departments of Medicine & Physiology, University of California , San Francisco, California 94143, United States.
authors.forename: Onur
authors.initials: O
authors.lastname: Cil
authors.affiliation: Department of Chemistry, University of California , Davis, California 95616, United States.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Teuthorn
authors.affiliation: Department of Chemistry, University of California , Davis, California 95616, United States.
authors.forename: Colton K
authors.initials: CK
authors.lastname: Ku
authors.affiliation: Departments of Medicine & Physiology, University of California , San Francisco, California 94143, United States.
authors.forename: Sujin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Departments of Medicine & Physiology, University of California , San Francisco, California 94143, United States.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Verkman
authors.affiliation: Department of Chemistry, University of California , Davis, California 95616, United States.
authors.forename: Mark J
authors.identifier: 0000-0001-8496-6125
authors.initials: MJ
authors.lastname: Kurth
mesh_terms: D000208:Acute Disease; D000818:Animals; D002460:Cell Line; D003248:Constipation / Q000188:drug therapy / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000819:agonists* / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011810:Quinoxalines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D011810:Quinoxalines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator