Optimization of 2-piperidin-4-yl-acetamides as melanin-concentrating hormone receptor 1 (MCH-R1) antagonists: Designing out hERG inhibition

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 15, 2009, Pages 4268-4273

  Berglund, Susanne ^a   Egner, Bryan J ^a   Gradén, Henrik ^a   Gradén, Joakim ^a   Morgan, David G A ^b   Inghardt, Tord ^a   Giordanetto, Fabrizio ^a  

^a ASTRAZENECA R AND D   (Sweden)

^b ASTRAZENECA   (United Kingdom)

Author keywords

hERG inhibitor; MCH; MCH R1 antagonists; Melanin concentrating hormone; Obesity

Indexed keywords

2 PIPERIDIN 4 YL ACETAMIDE DERIVATIVE; MELANIN CONCENTRATING HORMONE RECEPTOR 1 ANTAGONIST; POTASSIUM CHANNEL HERG; UNCLASSIFIED DRUG;

ARTICLE; CONTROLLED STUDY; DRUG PENETRATION; DRUG SELECTIVITY; DRUG STABILITY; DRUG STRUCTURE; HUMAN; IN VITRO STUDY; IN VIVO STUDY;

ACETAMIDES; ANIMALS; ANTI-OBESITY AGENTS; CELL LINE; CHEMISTRY, PHARMACEUTICAL; CHO CELLS; CRICETINAE; CRICETULUS; DRUG DESIGN; ETHER-A-GO-GO POTASSIUM CHANNELS; HUMANS; INHIBITORY CONCENTRATION 50; MICE; MODELS, CHEMICAL; OBESITY; PIPERIDINES; RECEPTORS, PITUITARY HORMONE; TIME FACTORS;

EID: 67650146077     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.05.067     Document Type: Article

References (23)

1. Melnikova I., and Wages D. Nat. Drug Discovery 5 (2006) 369
2. Rivera G., Bocanegra-Garcia V., Galiano S., Cirauqui N., Ceras J., Perez S., Aldana I., and Monge A. Curr. Med. Chem. 15 (2008) 1025
3. Kowalski T.J., and Sasikumar T. Biodrugs 21 (2007) 311
4. Rokosz L.L. Exp. Opin. Drug Discovery 2 (2007) 1301
5. Souers A.J., Gao J., Brune M., Bush E., Wodka D., Vasudevan A., Judd A.S., Mulhern M., Brodjian S., Dayton B., Shapiro R., Hernandez L.E., Marsh K.C., Sham H.L., Collins C.A., and Kym P.R. J. Med. Chem. 48 (2005) 1318
6. Takekawa S., Asami A., Ishihara Y., Terauchi J., Kato K., Shimomura Y., Mori M., Murakoshi H., Kato K., Suzuki N., Nishimura O., and Fujino M. Eur. J. Pharmacol. 438 (2002) 129
7. Schwartz M.W., Woods S.C., Porte Jr. D., Selley R.J., and Baskin D.G. Nature 404 (2000) 661
8. Gomori A., Ishiara A., Ito M., Mashiko S., Matsuhita H., Yumoto M., Ito M., Tanaka T., Tokita S., Moriya M., Iwaasa H., and Kanatani A. Am. J. Physiol.: Endocrinol. Metab. 284 (2003) E583
9. Ludwig D.S., Tritos N.A., Mastaitis J.W., Kulkarni R., Kokkotou E., Elmiqst J., Lowell B., Flier J.S., and Maratos-Flier E. J. Clin. Invest. 107 (2001) 379
10. Shimada M., Tritos N.A., Lowell B.A., Flier J.S., and Maratos-Flier E. Nature 396 (1998) 670
11. Luthin D.R. Life Sci. 81 (2007) 423
12. Berglund S., Egner B.J., Gradén H., Gradén J., Morgan D.G.A., Inghardt T., and Giordanetto F. Bioorg. Med. Chem. Lett. 18 (2008) 4859
13. Berglund S., Egner B.J., Gradén H., Gradén J., Morgan D.G.A., Inghardt T., and Giordanetto F. Bioorg. Med. Chem. Lett. 19 (2009) 4274
14. Pearlstein R., and Vaz Rampe R. J. Med. Chem. 46 (2003) 2017
15. Redfern W.S., Carlsson L., Davis A.S., Lynch W.G., MacKenzie I., Palethorpe S., Seigl P.K.S., Strang I., Sullivan A.T., Wallis R., Camm A.J., and Hammond T.G. Cardiovasc. Res. 58 (2003) 32
16. Testai L., Bianucci A.M., Massarelli I., Breschi M.C., Martinotti E., and Calderone V. Curr. Med. Chem. 11 (2004) 2691
17. Mitcheson J.S., and Perry M.D. Curr. Opin. Drug Discovery Dev. 6 (2003) 667
18. Pearlstein R.A., Vaz R.J., Kang J., Chen X., Preobrazhenskaya M., Shchekotikhin A.E., Korolev A.M., Lysenkova L.N., Miroshnikova O.V., Hendrix J., and Rampe D. Bioorg. Med. Chem. Lett. 13 (2003) 1829
19. Springthorpe, B. Abstract of Papers, 232nd National Meeting of the American Chemical Society, San Francisco, CA, 2006; Abstract 0044.
20. Jamieson C., Moir A.M., Rankovic Z., and Wishart G. J. Med. Chem. 49 (2006) 5029
21. Brickmann, K.; Egner, B. J.; Giordanetto F.; Inghardt, T.; Linusson, A.; Ponten, F. WO2005090330; Egner, B. J.; Giordanetto, F.; Inghardt, T. WO2006068594.
22. Wan H., Holmén A., Wang Y.D., Lindberg W., Englund M., Någård M., and Thompson R. Rapid Commun. Mass Spectrom. 1 (2003) 2639
23. Measurement of body weight and food intake. Mice used for weight-gain studies were housed three to four per cage and given free access to standard mouse chow containing 4% of total energy as fat (R-34; Lactamin AB, Stockholm, Sweden) or to cafeteria diet, an ad libitum choice of standard mouse chow, full-fat cheese (38% fat), almond paste, milk chocolate, and pastry (Delicatobollar; Delicato, Solna, Sweden) based on vegetarian butter, sugar, rolled oats, cocoa, and coconut shreds). From 4 wk of age, mice were weighed weekly to the nearest 0.1 g on an electronic scale. Treatment of mice began after 10 weeks on diet. Mice were dosed with compound or vehicle per os, once daily, 90-60 min before the onset of dark.