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Phenylquinoxalinone CFTR activator as potential prosecretory therapy for constipation.


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.

SUBMITTER: Cil O 

PROVIDER: S-EPMC5453637 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Phenylquinoxalinone CFTR activator as potential prosecretory therapy for constipation.

Cil Onur O   Phuan Puay-Wah PW   Son Jung-Ho JH   Zhu Jie S JS   Ku Colton K CK   Tabib Niloufar Akhavan NA   Teuthorn Andrew P AP   Ferrera Loretta L   Zachos Nicholas C NC   Lin Ruxian R   Galietta Luis J V LJV   Donowitz Mark M   Kurth Mark J MJ   Verkman Alan S AS  

Translational research : the journal of laboratory and clinical medicine 20161015


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 c  ...[more]

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