The efficacy and cardiac evaluation of aminomethyl tetrahydronaphthalene ketopiperazines: A novel class of potent MCH-R1 antagonists

Bioorganic and Medicinal Chemistry

Volumn 15, Issue 5, 2007, Pages 2092-2105

  Méndez Andino, José L ^a   Colson, Anny Odile ^a   Meyers, Kenneth M ^a   Mitchell, Maria C ^a   Hodge, Karen ^a   Howard, Jeremy M ^a   Kim, Nicholas ^a   Ackley, David C ^a   Holbert, Jerry K ^a   Mittelstadt, Scott W ^a   Dowty, Martin E ^a   Obringer, Cindy M ^a   Suchanek, Paula ^a   Reizes, Ofer ^a   Eric Hu, X ^a   Wos, John A ^a  

^a PROCTER AND GAMBLE PHARMACEUTICALS   (United States)

Author keywords

hERG; MCH R1 antagonists; Melanin concentrating hormone; Obesity; QT interval prolongation

Indexed keywords

4 (4 FLUOROPHENETHYL) 1 [6 [(DIETHYLAMINO)METHYL] 1,2,3,4 TETRAHYDRONAPHTHALEN 2 YL]PIPERAZIN 2 ONE; ANTIOBESITY AGENT; MELANIN CONCENTRATING HORMONE; MELANIN CONCENTRATING HORMONE RECEPTOR 1; MELANIN CONCENTRATING HORMONE RECEPTOR 1 ANTAGONIST; RECEPTOR BLOCKING AGENT; TETRALIN DERIVATIVE; UNCLASSIFIED DRUG;

AMINO ACID SEQUENCE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CARBON NUCLEAR MAGNETIC RESONANCE; CELL STRAIN CACO 2; CONTROLLED STUDY; DISEASE MODEL; DOG; DRUG BLOOD LEVEL; DRUG DESIGN; DRUG DOSE COMPARISON; DRUG EFFECT; DRUG EFFICACY; DRUG PENETRATION; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; EVALUATION; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; IC 50; MALE; MOUSE; NONHUMAN; OBESITY; QT INTERVAL; QT PROLONGATION; RECEPTOR AFFINITY; SEQUENCE ANALYSIS; SPRAGUE DAWLEY RAT; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS; WEIGHT REDUCTION;

ANIMALS; DOGS; DRUG EVALUATION, PRECLINICAL; MAGNETIC RESONANCE SPECTROSCOPY; MALE; MASS SPECTROMETRY; MODELS, MOLECULAR; PIPERAZINES; RECEPTORS, SOMATOSTATIN; STRUCTURE-ACTIVITY RELATIONSHIP;

CANIS FAMILIARIS;

EID: 33846638308     PISSN: 09680896     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmc.2006.12.028     Document Type: Article

References (37)

1. The Surgeon General's Call to Action to Prevent and Decrease Overweight and Obesity 2001, Public Health Service: Office of the Surgeon General, U.S. Department of Health and Human Sevices: Rockville, MD, 2001; www.surgeongeneral.gov/topics/obesity.
2. Powell D.R. Obes. Rev. 7 (2006) 89-108
3. Fong T.M. Expert Opin. Investig. Drugs 14 (2005) 243
4. Heal D.J., Rowley H.L., and Jackson H.C. Prog. Obes. Res. 9 (2003) 260-264
5. Dyke H.J., and Ray N.C. Expert Opin. Ther. Patents 15 (2005) 1303
6. Carpenter A.J., and Hertzog D.L. Expert Opin. Ther. Patents 12 (2002) 1639
7. Saito Y., Nothacker H.-P., and Civelli O. Trends Endocrinol. Metab. 11 (2000) 299
8. Schwartz M.W., Woods S.C., Porte Jr. D., Selley R.J., and Baskin D.G. Nature 404 (2000) 661
9. Kowalski T.J., and McBriar M.D. Expert Opin. Investig. Drugs 13 (2004) 1113
10. Receveur J.M., Bjurling E., Ulven T., Little P.B., Nørregaard P.K., and Högberg T. Bioorg. Med. Chem. Lett. 14 (2004) 5075
11. Shearman L.P., Camacho R.E., Sloan S.D., Zhou D., Bednarek M.A., Hreniuk D.L., Feighner S.D., Tan C.P., Howard A.D., Van der Ploeg L.H., MacIntyre D.E., Hickey G.J., and Strack A.M. Eur. J. Pharmacol. 475 (2003) 37
12. Handlon A.L., and Zhou H. J. Med. Chem. 49 (2006) 4017-4022
13. Dyck B., Markison S., Zhao L., Tamiya J., Grey J., Rowbottom M.W., Zhang M., Vickers T., Sorensen K., Norton C., Wen J., Heise C.E., Saunders J., Conlon P., Madan A., Schwarz D., and Goodfellow V.S. J. Med. Chem. 49 (2006) 3753-3756
14. Kym P.R., Souers A.J., Campbell T.J., Lynch J.K., Judd A.S., Iyengar R., Vasudevan A., Gao J., Freeman J.C., Wodka D., Mulhern M., Zhao G., Wagaw S.H., Napier J.J., Brodjian S., Dayton B.D., Reilly R.M., Segreti J.A., Fryer R.M., Preusser L.C., Reinhart G.A., Hernandez L., Marsh K.C., Sham H.L., Collins C.A., and Polakowski J.S. J. Med. Chem. 49 (2006) 2339-2352
15. McBriar M.D., Guzik H., Shapiro S., Paruchova J., Xu R., Palani A., Clader J.W., Cox K., Greenlee W.J., Hawes B.E., Kowalski T.J., O'Neill K., Spar B.D., Weig B., Weston D.J., Farley C., and Cook J. J. Med. Chem. 49 (2006) 2294-2310
16. Ulven T., Little P.B., Receveur J.-M., Frimurer T.M., Rist Ø., Nørregaard P.K., and Högberg T. Bioorg. Med. Chem. Lett. 16 (2006) 1070
17. Lynch J.K., Freeman J.C., Judd A.S., Iyengar R., Mulhern M., Zhao G., Napier J.J., Wodka D., Brodjian S., Dayton B.D., Falls D., Ogiela C., Reilly R.M., Campbell T.J., Polakowski J.S., Hernandez L., Marsh K.C., Shapiro R., Knourek-Segel V., Droz B., Bush E., Brune M., Preusser L.C., Fryer R.M., Reinhart G.A., Houseman K., Diaz G., Mikhail A., Limberis J.T., Sham H.L., Collins C.A., and Kym P.R. J. Med. Chem. 49 (2006) 6569-6584
18. Hu, X. E. US 2005075324, 2005.
19. Stenkamp, D.; Lehmann-Lintz, T.; Mueller, S.; Rudolf, K.; Lustenberger, P.; Arndt, K.; Lotz, R.; Wieland, H.; Lenter, M. DE 10238865, 2004.
20. Kato, K.; Terauchi, J.; Mori, M.; Suzuki, N.; Shimomura, Y.; Takekawa, S.; Ishihara, Y. WO 2001021577, 2001.
21. Ulven T., Frimurer T.M., Receveur J.-M., Little P.B., Rist Ø., Nørregaard P.K., and Högberg T. J. Med. Chem. 48 (2005) 5684
22. Mieling, G. E.; Mieling, K. K.; Bush, R. D.; Colson, A. O. US 2005170433 A1 2005.
23. i) and maximal efficacy were determined and used to define structure-activity relationship.
24. Caco-2 determinations having a compound target concentration equal to 1 μg/mL:. Artursson P., Palm K., and Luthman K. Adv. Drug Delivery Rev. 46 (2001) 27
25. Within our MCH program, we observed that compounds predicted to transport passively across the blood-brain barrier in the Caco-2 assay usually promoted statistically significant weight loss in our 4 day mDIO model, and displayed [brain]/[serum] > 2. Compounds predicted efflux substrates did not show in vivo activity and displayed [brain]/[serum] < 1. Please refer to: Meyers, K. M.; Méndez-Andino, J. L.; Colson, A. O.; Warshakoon, N. C.; Wos, J. A.; Mitchell, M. C.; Hodge, K. M.; Howard, J. M.; Ackley, D. C; Holbert, J. K.; Mittelstadt, S. W.; Dowty, M. E.; Obringer, C. M.; Ofer Reizes, O.; Hu, X. E. Bioorg. Med. Chem. Lett., in press.
26. c log P values were determined in Advanced Chemistry Development, ACD log D, version 9.0, www.acdlabs.com.
27. 50 determinations were carried out as described in:. Zhou Z., Gong Q., Ye B., Fan Z., Makielski J.C., Robertson G.A., and January C.T. Biophys. J. 74 (1998) 230
28. Nicholson J.R., Kohler G., Schaerer F., Senn C., Weyermann P., and Hofbauer K.G. J. Pharmacol. Exp. Ther. 317 (2006) 771
29. Tinsley F.C., Taicher G.Z., and Heiman M.L. Obes. Res. 12 (2004) 150
30. Heiland S., Sartor K., Martin E., Bardenheuer H.J., and Plaschke K. Neurosci. Lett. 334 (2002) 157-160
31. Scheneider J., Hauser R., Andreas J.-O., Linz K., and Jahnel U. Eur. J. Phamacol. 512 (2005) 53
32. Haverkamp W., Breithardt G., Camm A.J., Janse M.J., Rosen M.R., Antzelevitch C., Escande D., Malik Franz M., Moss A., and Shah R. Cardiovasc. Res. 47 (2000) 219
33. Shah R.R. Br. J. Clin. Pharmacol. 54 (2002) 188
34. Tashibu H., Miyazaki H., Aoki K., Akie Y., and Yamamoto K. J. Pharmacol. Sci. (2005) 473-486
35. Spence S., Soper K., Hoe C.-M., and Coleman J. Toxicol. Sci. 45 (1998) 247-258
36. Palczewski K., Kumasaka T., Hori T., Behnke C.A., Motoshima H., Fox B.A., Le Trong I., Teller D.C., Okada T., Stenkamp R.E., Yamamoto M., and Miyano M. Science 289 (2000) 739-745
37. Macdonald D., Murgolo N., Zhang R., Durkin J.P., Yao X., Strader C.D., and Graziano M.P. Mol. Pharmacol. 58 (2000) 217-225