Phenylquinoxalinone CFTR activator as potential prosecretory therapy for constipation

Onur Cil, Puay Wah Phuan, Jung Ho Son, Jie S. Zhu, Colton K. Ku, Niloufar Akhavan Tabib, Andrew P. Teuthorn, Loretta Ferrera, Nicholas C. Zachos, Ruxian Lin, Luis J V Galietta, Mark Donowitz, Mark J. Kurth, Alan S. Verkman

Research output: Contribution to journalArticle

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Abstract

Constipation is a common condition for which current treatments can have limited efficacy. By high-throughput screening, we recently identified a phenylquinoxalinone activator of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel that stimulated intestinal fluid secretion and normalized stool output in a mouse model of opioid-induced constipation. Here, we report phenylquinoxalinone structure-activity analysis, mechanism of action, animal efficacy data in acute and chronic models of constipation, and functional data in ex vivo primary cultured human enterocytes. Structure-activity analysis was done on 175 phenylquinoxalinone analogs, including 15 synthesized compounds. The most potent compound, CFTRact-J027, activated CFTR with EC50∼ 200 nM, with patch-clamp analysis showing a linear CFTR current-voltage relationship with direct CFTR activation. CFTRact-J027 corrected reduced stool output and hydration in a mouse model of acute constipation produced by scopolamine and in a chronically constipated mouse strain (C3H/HeJ). Direct comparison with the approved prosecretory drugs lubiprostone and linaclotide showed substantially greater intestinal fluid secretion with CFTRact-J027, as well as greater efficacy in a constipation model. As evidence to support efficacy in human constipation, CFTRact-J027 increased transepithelial fluid transport in enteroids generated from normal human small intestine. Also, CFTRact-J027 was rapidly metabolized in vitro in human hepatic microsomes, suggesting minimal systemic exposure upon oral administration. These data establish structure-activity and mechanistic data for phenylquinoxalinone CFTR activators, and support their potential efficacy in human constipation.

Original languageEnglish (US)
Pages (from-to)14-26.e4
JournalTranslational Research
Volume182
DOIs
StatePublished - Apr 1 2017

Fingerprint

Cystic Fibrosis Transmembrane Conductance Regulator
Constipation
Intestinal Secretions
Fluids and Secretions
Fluids
Therapeutics
Chloride Channels
Scopolamine Hydrobromide
Clamping devices
Hydration
Opioid Analgesics
Inbred C3H Mouse
Enterocytes
Screening
Animals
Chemical activation
Microsomes
Throughput
Small Intestine
Oral Administration

ASJC Scopus subject areas

  • Medicine(all)
  • Public Health, Environmental and Occupational Health
  • Biochemistry, medical

Cite this

Cil, O., Phuan, P. W., Son, J. H., Zhu, J. S., Ku, C. K., Tabib, N. A., ... Verkman, A. S. (2017). Phenylquinoxalinone CFTR activator as potential prosecretory therapy for constipation. Translational Research, 182, 14-26.e4. https://doi.org/10.1016/j.trsl.2016.10.003

Phenylquinoxalinone CFTR activator as potential prosecretory therapy for constipation. / Cil, Onur; Phuan, Puay Wah; Son, Jung Ho; Zhu, Jie S.; Ku, Colton K.; Tabib, Niloufar Akhavan; Teuthorn, Andrew P.; Ferrera, Loretta; Zachos, Nicholas C.; Lin, Ruxian; Galietta, Luis J V; Donowitz, Mark; Kurth, Mark J.; Verkman, Alan S.

In: Translational Research, Vol. 182, 01.04.2017, p. 14-26.e4.

Research output: Contribution to journalArticle

Cil, O, Phuan, PW, Son, JH, Zhu, JS, Ku, CK, Tabib, NA, Teuthorn, AP, Ferrera, L, Zachos, NC, Lin, R, Galietta, LJV, Donowitz, M, Kurth, MJ & Verkman, AS 2017, 'Phenylquinoxalinone CFTR activator as potential prosecretory therapy for constipation', Translational Research, vol. 182, pp. 14-26.e4. https://doi.org/10.1016/j.trsl.2016.10.003
Cil, Onur ; Phuan, Puay Wah ; Son, Jung Ho ; Zhu, Jie S. ; Ku, Colton K. ; Tabib, Niloufar Akhavan ; Teuthorn, Andrew P. ; Ferrera, Loretta ; Zachos, Nicholas C. ; Lin, Ruxian ; Galietta, Luis J V ; Donowitz, Mark ; Kurth, Mark J. ; Verkman, Alan S. / Phenylquinoxalinone CFTR activator as potential prosecretory therapy for constipation. In: Translational Research. 2017 ; Vol. 182. pp. 14-26.e4.
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AU - Cil, Onur

AU - Phuan, Puay Wah

AU - Son, Jung Ho

AU - Zhu, Jie S.

AU - Ku, Colton K.

AU - Tabib, Niloufar Akhavan

AU - Teuthorn, Andrew P.

AU - Ferrera, Loretta

AU - Zachos, Nicholas C.

AU - Lin, Ruxian

AU - Galietta, Luis J V

AU - Donowitz, Mark

AU - Kurth, Mark J.

AU - Verkman, Alan S.

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N2 - Constipation is a common condition for which current treatments can have limited efficacy. By high-throughput screening, we recently identified a phenylquinoxalinone activator of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel that stimulated intestinal fluid secretion and normalized stool output in a mouse model of opioid-induced constipation. Here, we report phenylquinoxalinone structure-activity analysis, mechanism of action, animal efficacy data in acute and chronic models of constipation, and functional data in ex vivo primary cultured human enterocytes. Structure-activity analysis was done on 175 phenylquinoxalinone analogs, including 15 synthesized compounds. The most potent compound, CFTRact-J027, activated CFTR with EC50∼ 200 nM, with patch-clamp analysis showing a linear CFTR current-voltage relationship with direct CFTR activation. CFTRact-J027 corrected reduced stool output and hydration in a mouse model of acute constipation produced by scopolamine and in a chronically constipated mouse strain (C3H/HeJ). Direct comparison with the approved prosecretory drugs lubiprostone and linaclotide showed substantially greater intestinal fluid secretion with CFTRact-J027, as well as greater efficacy in a constipation model. As evidence to support efficacy in human constipation, CFTRact-J027 increased transepithelial fluid transport in enteroids generated from normal human small intestine. Also, CFTRact-J027 was rapidly metabolized in vitro in human hepatic microsomes, suggesting minimal systemic exposure upon oral administration. These data establish structure-activity and mechanistic data for phenylquinoxalinone CFTR activators, and support their potential efficacy in human constipation.

AB - Constipation is a common condition for which current treatments can have limited efficacy. By high-throughput screening, we recently identified a phenylquinoxalinone activator of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel that stimulated intestinal fluid secretion and normalized stool output in a mouse model of opioid-induced constipation. Here, we report phenylquinoxalinone structure-activity analysis, mechanism of action, animal efficacy data in acute and chronic models of constipation, and functional data in ex vivo primary cultured human enterocytes. Structure-activity analysis was done on 175 phenylquinoxalinone analogs, including 15 synthesized compounds. The most potent compound, CFTRact-J027, activated CFTR with EC50∼ 200 nM, with patch-clamp analysis showing a linear CFTR current-voltage relationship with direct CFTR activation. CFTRact-J027 corrected reduced stool output and hydration in a mouse model of acute constipation produced by scopolamine and in a chronically constipated mouse strain (C3H/HeJ). Direct comparison with the approved prosecretory drugs lubiprostone and linaclotide showed substantially greater intestinal fluid secretion with CFTRact-J027, as well as greater efficacy in a constipation model. As evidence to support efficacy in human constipation, CFTRact-J027 increased transepithelial fluid transport in enteroids generated from normal human small intestine. Also, CFTRact-J027 was rapidly metabolized in vitro in human hepatic microsomes, suggesting minimal systemic exposure upon oral administration. These data establish structure-activity and mechanistic data for phenylquinoxalinone CFTR activators, and support their potential efficacy in human constipation.

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