Discovery of novel orally active ureido NPY Y5 receptor antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 3, 2008, Pages 1146-1150

  Li, Guoqing ^a   Stamford, Andrew W ^a   Huang, Ying ^a   Cheng, Kuo Chi ^a   Cook, John ^a   Farley, Constance ^a   Gao, Jun ^a   Ghibaudi, Lorraine ^a   Greenlee, William J ^a   Guzzi, Mario ^a   van Heek, Margaret ^a   Hwa, Joyce J ^a   Kelly, Joe ^a   Mullins, Deborra ^a   Parker, Eric M ^a   Wainhaus, Sam ^a   Zhang, Xiaoping ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Neuropeptide Y; NPY Y5 antagonist; Obesity

Indexed keywords

HORMONE RECEPTOR BLOCKING AGENT; NEUROPEPTIDE Y5 RECEPTOR; NEUROPEPTIDE Y5 RECEPTOR ANTAGONIST; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BODY WEIGHT; CONTROLLED STUDY; DOG; DRUG IDENTIFICATION; DRUG MECHANISM; DRUG POTENCY; DRUG SCREENING; FAT BODY; FOOD INTAKE; LEAN BODY WEIGHT; MALE; NONHUMAN; OBESITY; RAT; WEIGHT GAIN;

ADMINISTRATION, ORAL; ANIMALS; ANTI-OBESITY AGENTS; COMBINATORIAL CHEMISTRY TECHNIQUES; DOGS; HUMANS; MICE; MOLECULAR STRUCTURE; OBESITY; RATS; RECEPTORS, NEUROPEPTIDE Y; STRUCTURE-ACTIVITY RELATIONSHIP; UREA;

CANIS FAMILIARIS; RATTUS;

EID: 38749139889     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.11.132     Document Type: Article

References (19)

1. Tatemoto K., Carlquist M., and Mutt V. Nature 296 (1982) 659-661
2. Blomqvist A.G., and Herzog H. Trends Neurosci. 20 (1997) 294
3. Gerald C., Walker M.W., Criscione L., Gustafson E.L., Batzl-Hartmann C., Smith K.E., Vaysse P., Durkin M.M., Laz T.M., Linemeyer D.L., Schaffhauser A.O., whitebread S., Hofbauer K.G., Taber R.I., Branchek T.A., and Weinshank R.L. Nature 382 (1996) 168
4. Hwa J.J., Witten M.B., Williams P., Ghibaudi L., Gao J., Salisbury B.G., Mullins D., Hamud F., Strader C.D., and Parker E.M. Am. J. Physiol. 277 (1999) R1428
5. Mashiko S., Ishihara A., Iwaasa H., Sano H., Oda Z., Ito J., Yumoto M., Okawa M., Suzuki J., Fukuroda T., Jitsuoka M., Morin N.R., MacNeil D.J., Van der Ploeg L.H.T., Ihara M., Fukami T., and Kanatani A. Endocrinology 144 (2003) 1793
6. Parker E., van Heek M., and Stamford A. Eur. J. Pharmacol. 440 (2002) 173
7. Stamford W.A., Hwa J., and van Heek M. Ann. Rep. Med. Chem. 38 (2003) 61
8. Rueeger H., Gerspacher M., Buehlmayer P., Rigollier P., Yamaguchi Y., Schmidlin T., Whitebread S., Nusslein-Hildesheim B., Nick H., and Cricione L. Bioorg. Med. Chem. Lett. 14 (2004) 2451
9. Gillman K.W., Higgins M.A., Poindexter G.S., Browning M., Clarke W.J., Flowers S., James Jr. G.E., Hogan J.B., McGovern R.T., Iben L.G., Mattson G.K., Ortiz A., Rassnick S., Russell J.W., and Antal-Zimanyi I. Biorg. Med. Chem. 14 (2006) 5517
10. Kakui N., Tanaka J., Tabata Y., Asai K., Masuda N., Miyara T., Nakatani Y., Ohsawa F., Nishikawa N., Sugai M., Suzuki M., Aoki K., and Kitaguchi H. J. Pharmacol. Exp. Ther. 317 (2006) 562
11. Ishihara A., Kanatani A., Mashiko S., Tanaka T., Hidaka M., Gomori A., Iwaasa H., Murai N., Egashira S.-I., Murai T., Mitobe Y., Matsushita H., Okamoto O., Sato N., Jitsuoka M., Fukuroda T., Ohe T., Guan X., MacNeil D.J., Van der Ploeg L.H.T., Nishikibe M., Ishii Y., Ihara M., and Fukami T. Proc. Natl. Acad. Sci. U.S.A. 103 (2006) 7154
12. Mashiko S., Ishihara A., Iwaasa H., Sano H., Ito J., Gomori A., Oda Z., Moriya R., Matsushita H., Jitsuoka M., Okamoto O., MacNeil D.J., Van der Ploeg L.H.T., Fukami T., and Kanatani A. Mol. Pharmacol. 71 (2007) 602
13. Erondu N., Gantz I., Musser B., Suryawanshi S., Mallick M., Addy C., Cote J., Bray G., Fujioka K., Bays H., Hollander P., Sanabria-Bohorquez S.M., Eng W., Langstrom B., Hargreaves R.J., Burns H.D., Kanatani A., Fukami T., MacNeil D.J., Gottesdiener K.M., Amatruda J.M., Kaufman K.D., and Heymsfield S.B. Cell Metab. 4 (2006) 275
14. Greenlee, W. J.; Huang, Y; Kelly, J. M.; McCombie, S. W.; Stamford, A. W.; Wu, Y. PCT Int. Appl. 2002, WO 2002022592.
15. 5 receptor. Parker E.M., Babij C.K., Balasubramaniam A., Burrier R.E., Guzzi M., Hamud F., Mukhopadhyay G., Rudinski M.S., Tao Z., Tice M., Xia L., Mullins D.E., and Salisbury B.G. Eur. J. Pharmacol. 349 (1998) 97
16. Parker E.M., Balasubramanian A., Guzzi M., Mullins D.E., Salisbury B.G., Sheriff S., Witten M.B., and Hwa J.J. Peptides 21 (2000) 393
17. Cundy D.J., and Forsyth S.A. Tetrahedron Lett. 39 (1998) 7979
18. -).
19. Ghibaudi L., Cook J., Farley C., van Heek M., and Hwa J.J. Obesity Res. 10 (2002) 956 Male Sprague-Dawley rats were raised on a 45% high fat diet (Research Diets, New Brunswick, NJ; D12451) for five months, followed by a three-week 10% low fat (Research Diets; D12450B) run in, prior to commencing the 28-day study. At the start of the study, the rats (n = 12/group) weighed 700-800 g; animals were offered food and water ad libitum throughout the study. Compound 21c was admixed into low fat diet (Research Diets); doses delivered (1, 3, or 10 mg/kg/day) were calculated based on food consumption during the treatment period. Average plasma levels of 21c were approximately 13 μM at the 10 mg/kg/day dose. Body composition was determined by DEXA scanning; data are expressed as percent change from t = day 0 baseline