Format

Send to

Choose Destination
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.

Author information

1
Departments of Medicine and Physiology, University of California San Francisco, San Francisco, Calif.
2
Department of Chemistry, University of California, Davis, Calif.
3
Istituto Giannina Gaslini, Genova, Italy.
4
Departments of Physiology and Medicine, Gastroenterology Division, Johns Hopkins University School of Medicine, Baltimore, Md.
5
Departments of Medicine and Physiology, University of California San Francisco, San Francisco, Calif. Electronic address: Alan.Verkman@ucsf.edu.

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.

PMID:
27815136
PMCID:
PMC5453637
DOI:
10.1016/j.trsl.2016.10.003
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center