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Transl Res. 2017 Apr;182:14-26.e4. doi: 10.1016/j.trsl.2016.10.003. Epub 2016 Oct 15.

Phenylquinoxalinone CFTR activator as potential prosecretory therapy for constipation.

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Departments of Medicine and Physiology, University of California San Francisco, San Francisco, Calif.
Department of Chemistry, University of California, Davis, Calif.
Istituto Giannina Gaslini, Genova, Italy.
Departments of Physiology and Medicine, Gastroenterology Division, Johns Hopkins University School of Medicine, Baltimore, Md.
Departments of Medicine and Physiology, University of California San Francisco, San Francisco, Calif. Electronic address:


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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