Orally active C-6 heteroaryl- and heterocyclyl-substituted imidazo[1,2-a]pyridine acid pump antagonists (APAs)

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 13, 2009, Pages 3602-3606

  Bailey, Nick ^a   Bamford, Mark J ^a   Brissy, Delphine ^a   Brookfield, Joanna ^a   Demont, Emmanuel ^a   Elliott, Richard ^a   Garton, Neil ^a   Farre Gutierrez, Irene ^a   Hayhow, Thomas ^a   Hutley, Gail ^a   Naylor, Antoinette ^a   Panchal, Terry A ^a   Seow, Hui Xian ^a   Spalding, David ^a   Takle, Andrew K ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

Acid pump antagonist; Imidazo 1,2 a pyridine; Potassium competitive acid blocker

Indexed keywords

8 (2,6 DIMETHYLBENZYLAMINO) N (2 HYDROXYETHYL) 2,3 DIMETHYLIMIDAZO[1,2 A]PYRIDINE 6 CARBOXAMIDE; CYTOCHROME P450 2C9; CYTOCHROME P450 3A4; HYDROGEN POTASSIUM ADENOSINE TRIPHOSPHATASE; IMIDAZO[1,2 A]PYRIDINE DERIVATIVE; PENTAGASTRIN; PROTON PUMP INHIBITOR;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; DOG; DRUG CLEARANCE; DRUG HALF LIFE; DRUG METABOLISM; HUMAN; HUMAN CELL; IC 50; LIVER MICROSOME METABOLISM; NONHUMAN; RAT; STOMACH ACID SECRETION; STOMACH PARIETAL CELL; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; DOGS; H(+)-K(+)-EXCHANGING ATPASE; HUMANS; HYDROGEN-ION CONCENTRATION; PROTON PUMP INHIBITORS; PYRIDINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

ANIMALIA;

EID: 66349112839     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.04.127     Document Type: Article

References (21)

1. Sachs G., Shin J.M., Vagin O., Lambrecht N., Yakubov I., and Munson K.J. Clin. Gastroenterol. 41 (2007) S226
2. Scarpignato C., Pelosini I., and Di Mario F. Dig. Dis. 24 (2006) 11
3. Parsons M.E., and Keeling D.J. Exp. Opin. Invest. Drugs 14 (2005) 411
4. Andersson K., and Carlsson E. Pharmacol. Ther. 108 (2005) 294
5. Gedda K., Briving C., Svensson K., Maxvall I., and Andersson K. Biochem. Pharmacol. 73 (2007) 198
6. Abelo A., Andersson M., Holmberg A.A., and Karlsson M.O. Eur. J. Pharm. Sci. 29 (2006) 91
7. Dent J., Kahrilas P.J., Hatlebakk J., Vakil N., Denison H., Franzen S., and Lundborg P. Am. J. Gastroenterol. 103 (2008) 20
8. Kahrilas P.J., Dent J., Lauritsen K., Malfertheiner P., Denison H., Franzen S., and Hasselgren G. Clin. Gastroenterol. Hepatol. 5 (2007) 1385-1391 and references cited therein
9. Andersson, K. Society for Medicines Research Symposium, September 21, London, UK, 2006.
10. 3A4 DEF assay uses Diethoxyfluorescein as CYP 3A4 substrate. The 3A4 7BQ assay uses 7-Benzyloxyquinoline.
11. 50 determination is done at pH 7.4. See:. Wallmark B., Briving C., Fryklund J., Munson K., Jackson R., Mendlein J., Rabon E., and Sachs G. J. Biol. Chem. 262 (1987) 2077
12. Briving C., Andersson B.-M., Nordberg P., and Wallmark B. Biochim. Biophys. Acta 946 (1988) 185
13. For related work, see:. Palmer A.M., Grobbel B., Jecke C., Brehm C., Zimmermann P.J., Buhr W., Feth M.P., Simon W.-A., and Kromer W. J. Med. Chem. 50 (2007) 6240
14. See also. Palmer A.M., Mu{combining double acute accent}nch G., Brehm C., Zimmermann P.J., Buhr W., Feth M.P., and Simon W.-A. Bioorg. Med. Chem. 16 (2008) 1511 and references cited therein
15. The conditions of reactions were identical to conditions (i), Scheme 1.
16. Typically groups of male Wistar rats weighing 150 ± 20 g are fasted overnight prior to use in groups of 3. Test substance or vehicle (2% tween80 + 98% water) is administrated by oral gavage at 60 min before challenge with pentagastrin (5 μg/kg i.p.). Gastric acidity in individual samples (mEq HCl/ml) is titrated 10 min later. For procedures used in in vitro assays, see: Bamford, M. J.; Elliott, R. L.; Giblin, G. M. P.; Naylor, A.; Witherington, J.; Panchal, T. A.; Demont, E. H. PCT Int. Appl., WO 2006100119A1, 2006.
17. 50s against 2C9, 3A4 DEF and 7BQ are reported in the rest of the manuscript.
18. For first report of SAR in the imidazo[1,2-a]pyridine series, see:. Kaminski J.J., Bristol J.A., Puchalski C., Lovey R.G., Elliott A.J., Guzik H., Solomon D.M., Conn D.J., Domalski M.S., Wong S.-C., Gold E.H., Long J.F., Chiu P.J.S., Steinberg M., and McPhail A.T. J. Med. Chem. 28 (1985) 876
19. Kaminski J.J., and Doweyko A.M. J. Med. Chem. 40 (1997) 427-436
20. Kaminski, J. J.; Wallmark, B.; Briving, C.; Andersson, B.-M. J. Med. Chem. 1991, 34, 533-541. Compounds 40 and 41 were obtained from the corresponding chiral C-6 Bromo derivative (most potent isomer obtained by chiral chromatography from the racemic mixture). See: Buhr, W.; Zimmermann, P. J.; Brehm, C.; Palmer, A.; Kromer, W.; Postius, S.; Simon, W.-A. PCT Int. Appl., WO 2005077949A1, 2005 and references cited therein
21. 2 groups but have shown that these substituents can lead to liver toxicity: see. Kaminski J.J., Perkins D.G., Frantz J.D., Solomon D.M., Elliott A.J., Chiu P.J.S., Long J.F. J. Med. Chem. 30 (1987) 2047-2051 and references cited therein