• 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, GaliettaLuis J VLJVIstituto Giannina Gaslini, Genova, Italy., Mark Donowitz, Mark J Kurth, and Alan S Verkman.
• Departments of Medicine and Physiology, University of California San Francisco, San Francisco, Calif.
• Transl Res. 2017 Apr 1; 182: 1426.e414-26.e4.

AbstractConstipation 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.Copyright © 2016 Elsevier Inc. All rights reserved.

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