title: Benzopyrimido-pyrrolo-oxazine-dione CFTR inhibitor (R)-BPO-27 for antisecretory therapy of diarrheas caused by bacterial enterotoxins.
abstract: Secretory diarrheas caused by bacterial enterotoxins, including cholera and traveler's diarrhea, remain a major global health problem. Inappropriate activation of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel occurs in these diarrheas. We previously reported that the benzopyrimido-pyrrolo-oxazinedione (R)-BPO-27 inhibits CFTR chloride conductance with low-nanomolar potency. Here, we demonstrate using experimental mouse models and human enterocyte cultures the potential utility of (R)-BPO-27 for treatment of secretory diarrheas caused by cholera and Escherichia coli enterotoxins. (R)-BPO-27 fully blocked CFTR chloride conductance in epithelial cell cultures and intestine after cAMP agonists, cholera toxin, or heat-stable enterotoxin of E. coli (STa toxin), with IC50down to ∼5 nM. (R)-BPO-27 prevented cholera toxin and STa toxin-induced fluid accumulation in small intestinal loops, with IC50down to 0.1 mg/kg. (R)-BPO-27 did not impair intestinal fluid absorption or inhibit other major intestinal transporters. Pharmacokinetics in mice showed >90% oral bioavailability with sustained therapeutic serum levels for >4 h without the significant toxicity seen with 7-d administration at 5 mg/kg/d. As evidence to support efficacy in human diarrheas, (R)-BPO-27 blocked fluid secretion in primary cultures of enteroids from human small intestine and anion current in enteroid monolayers. These studies support the potential utility of (R)-BPO-27 for therapy of CFTR-mediated secretory diarrheas.-Cil, O., Phuan, P.-W., Gillespie, A. M., Lee, S., Tradtrantip, L., Yin, J., Tse, M., Zachos, N. C., Lin, R., Donowitz, M., Verkman, A. S. Benzopyrimido-pyrrolo-oxazine-dione CFTR inhibitor (R)-BPO-27 for antisecretory therapy of diarrheas caused by bacterial enterotoxins.
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, USA.|Department of Physiology, University of California San Francisco, San Francisco, California, USA.
authors.forename: Onur
authors.initials: O
authors.lastname: Cil
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, USA.|Department of Physiology, University of California San Francisco, San Francisco, California, USA.
authors.forename: Puay-Wah
authors.initials: PW
authors.lastname: Phuan
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, USA.|Department of Physiology, University of California San Francisco, San Francisco, California, USA.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Gillespie
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, USA.|Department of Physiology, University of California San Francisco, San Francisco, California, USA.
authors.forename: Sujin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, USA.|Department of Physiology, University of California San Francisco, San Francisco, California, USA.
authors.forename: Lukmanee
authors.initials: L
authors.lastname: Tradtrantip
authors.affiliation: Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; and.|Gastroenterology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Jianyi
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; and.|Gastroenterology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Tse
authors.affiliation: Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; and.|Gastroenterology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Zachos
authors.affiliation: Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; and.|Gastroenterology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Ruxian
authors.initials: R
authors.lastname: Lin
authors.affiliation: Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; and.|Gastroenterology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Donowitz
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, USA; alan.verkman@ucsf.edu.|Department of Physiology, University of California San Francisco, San Francisco, California, USA.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors*; D003967:Diarrhea / Q000139:chemically induced* / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007422:Intestines / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D010078:Oxazines / Q000138:chemical synthesis / Q000494:pharmacology*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: C000622182:(R)-BPO-27; D010078:Oxazines; D011744:Pyrimidinones; D011758:Pyrroles; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: cholera; intestinal secretion; secretory diarrhea; traveler’s diarrhea