CFTR Activator Increases Intestinal Fluid Secretion and Normalizes Stool Output in a Mouse Model of Constipation

Cellular and Molecular Gastroenterology and Hepatology

Volumn 2, Issue 3, 2016, Pages 317-327

  Cil, Onur ^a   Phuan, Puay Wah ^a   Lee, Sujin ^a   Tan, Joseph ^a   Haggie, Peter M ^a   Levin, Marc H ^a   Sun, Liang ^b   Thiagarajah, Jay R ^c   Ma, Tonghui ^b   Verkman, Alan S ^a,d  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b DALIAN MEDICAL UNIVERSITY   (China)

^c BOSTON CHILDREN S HOSPITAL   (United States)

^d UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

CFTR; Constipation; High Throughput Screening; Loperamide

Indexed keywords

CHLORIDE CHANNEL STIMULATING AGENT; CYCLIC AMP; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR ACTIVATOR J 027; GASTROINTESTINAL AGENT; LOPERAMIDE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONSTIPATION; DEFECATION; DRUG EFFICACY; EC50; FECES; FEMALE; FLUID TRANSPORT; GASTROINTESTINAL TRANSIT; HIGH THROUGHPUT SCREENING; IN VITRO STUDY; INTESTINAL SECRETION; INTESTINE ABSORPTION; INTESTINE FLUID; INTESTINE MOTILITY; LIVER MICROSOME; METABOLIC STABILITY; MOUSE; MUSCLE CONTRACTILITY; NONHUMAN; PRIORITY JOURNAL; RAT; SECRETION (PROCESS); SHORT CIRCUIT CURRENT; WATER CONTENT;

EID: 84959487877     PISSN: None     EISSN: 2352345X     Source Type: Journal    
DOI: 10.1016/j.jcmgh.2015.12.010     Document Type: Article

References (27)

1. Pinto Sanchez M.I., Bercik P. Epidemiology and burden of chronic constipation. Can J Gastroenterol 2011, 25(Suppl B):11B-15B.
2. Mugie S.M., Di Lorenzo C., Benninga M.A. Constipation in childhood. Nat Rev Gastroenterol Hepatol 2011, 8:502-511.
3. Menees S., Saad R., Chey W.D. Agents that act luminally to treat diarrhoea and constipation. Nat Rev Gastroenterol Hepatol 2012, 9:661-674.
4. Castro J., Harrington A.M., Hughes P.A., et al. Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3',5'-monophosphate. Gastroenterology 2013, 145:1334-1346.
5. Busby R.W., Bryant A.P., Bartolini W.P., et al. Linaclotide, through activation of guanylate cyclase C, acts locally in the gastrointestinal tract to elicit enhanced intestinal secretion and transit. Eur J Pharmacol 2010, 649:328-335.
6. Fei G., Raehal K., Liu S., et al. Lubiprostone reverses the inhibitory action of morphine on intestinal secretion in guinea pig and mouse. J Pharmacol Exp Ther 2010, 334:333-340.
7. Thiagarajah J.R., Donowitz M., Verkman A.S. Secretory diarrhoea: mechanisms and emerging therapies. Nat Rev Gastroenterol Hepatol 2015, 12:446-457.
8. Field M., Fromm D., Al-Awqati Q., et al. Effect of cholera enterotoxin on ion transport across isolated ileal mucosa. J Clin Invest 1972, 51:796-804.
9. Rao M.C., Guandalini S., Smith P.L., et al. Mode of action of heat-stable Escherichia coli enterotoxin tissue and subcellular specificities and role of cyclic GMP. Biochim Biophys Acta 1980, 632:35-46.
10. Subramanya S.B., Rajendran V.M., Srinivasan P., et al. Differential regulation of cholera toxin-inhibited Na-H exchange isoforms by butyrate in rat ileum. Am J Physiol 2007, 293:G857-G863.
11. + exchange isoform activities by enteropathogenic E. coli in human intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 2004, 287:G370-G378.
12. Galietta L.J.V., Springsteel M.F., Eda M., et al. Novel CFTR chloride channel activators identified by screening of combinatorial libraries based on flavone and benzoquinolizinium lead compounds. J Biol Chem 2001, 276:19723-19728.
13. Esteva-Font C., Cil O., Phuan P.W., et al. Diuresis and reduced urinary osmolality in rats produced by small-molecule UT-A-selective urea transport inhibitors. FASEB J 2014, 28:3878-3890.
14. Ma T., Vetrivel L., Yang H., et al. High-affinity activators of cystic fibrosis transmembrane conductance regulator (CFTR) chloride conductance identified by high-throughput screening. J Biol Chem 2002, 277:37235-37241.
15. Namkung W., Park J., Seo Y., et al. Novel amino-carbonitrile-pyrazole identified in a small molecule screen activates wild-type and δF508 cystic fibrosis transmembrane conductance regulator in the absence of a cAMP agonist. Mol Pharmacol 2013, 84:384-392.
16. Camilleri M. Guanylate cyclase C agonists: emerging gastrointestinal therapies and actions. Gastroenterology 2015, 148:483-487.
17. - secretion by lubiprostone requires the cystic fibrosis transmembrane conductance regulator. Gastroenterology 2009, 137:976-985.
18. Lembo A.J., Schneier H.A., Shiff S.J., et al. Two randomized trials of linaclotide for chronic constipation. N Engl J Med 2011, 365:527-536.
19. Accessed December 2015. https://www.amitizahcp.com/efficacy-indication-1/.
20. Gras D., Chanez P., Vachier I., et al. Bronchial epithelium as a target for innovative treatments in asthma. Pharmacol Ther 2013, 140:290-305.
21. Srivastava A. Progressive familial intrahepatic cholestasis. J Clin Exp Hepatol 2014, 4:25-36.
22. Levin M.H., Verkman A.S. CFTR-regulated chloride transport at the ocular surface in living mice measured by potential differences. Invest Ophthalmol Vis Sci 2005, 46:1428-1434.
23. Lawrence D.S., Copper J.E., Smith C.D. Structure-activity studies of substituted quinoxalinones as multiple-drug-resistance antagonists. J Med Chem 2001, 44:594-601.
24. Botton G, Valeur E, Kergoat M. Preparation of quinoxalinone derivatives as insulin secretion stimulators useful for the treatment of diabetes. PCT Int Appl 2009, WO 2009109258 approval date: Sep 11, 2009 (patent).
25. Dudley DA, Edmunds JJ. Preparation of quinoxalinones as serine protease inhibitors for treatment of thrombotic disorders. PCT Int Appl 1999, WO 9950254 approval date: Oct 07, 1999 (patent).
26. Qin X., Hao X., Han H., et al. Design and synthesis of potent and multifunctional aldose reductase inhibitors based on quinoxalinones. J Med Chem 2015, 58:1254-1267.
27. Shaw A.D., Denning C.R., Hulme C. One-pot two-step synthesis of quinoxalinones and diazepinones via a tandem oxidative amidation-deprotection-cyclization sequence. Synthesis 2013, 45:459-462.