Benzopyrimido-pyrrolo-oxazine-dione CFTR inhibitor (R)-BPO-27 for antisecretory therapy of diarrheas caused by bacterial enterotoxins

• Published in: The FASEB journal Vol. 31; no. 2; p. 751
• Main Authors: Cil, Onur, Phuan, Puay-Wah, Gillespie, Anne Marie, Lee, Sujin, Tradtrantip, Lukmanee, Yin, Jianyi, Tse, Ming, Zachos, Nicholas C, Lin, Ruxian, Donowitz, Mark, Verkman, Alan S
• Format: Journal Article
• Language: English
• Published: United States 01.02.2017
• Subjects: Animals; Cystic Fibrosis Transmembrane Conductance Regulator - antagonists & inhibitors; Diarrhea - chemically induced; Diarrhea - drug therapy; Dose-Response Relationship, Drug; Female; Humans; Intestines - drug effects; Mice; Molecular Structure; Oxazines - chemical synthesis; Oxazines - pharmacology; Pyrimidinones - chemical synthesis; Pyrimidinones - pharmacology; Pyrroles - chemical synthesis; Pyrroles - pharmacology; secretory diarrhea; traveler’s diarrhea; cholera; intestinal secretion
• ISSN: 1530-6860
• DOI: 10.1096/fj.201600891R

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 IC down to ∼5 nM. (R)-BPO-27 prevented cholera toxin and STa toxin-induced fluid accumulation in small intestinal loops, with IC down 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.