Discovery of (2S)-N-[(1R)-2-[4-cyclohexyl-4-[[(1,1-dimethylethyl)amino] carbonyl]-1-piperidinyl]-1-[(4-fluorophenyl)methyl]-2-oxoethyl] -4-methyl-2-piperazinecarboxamide (MB243), a potent and selective melanocortin subtype-4 receptor agonist

Bioorganic and Medicinal Chemistry Letters

Volumn 15, Issue 1, 2005, Pages 171-175

  Palucki, Brenda L ^a   Park, Min K ^a   Nargund, Ravi P ^a   Ye, Zhixiong ^a   Sebhat, Iyassu K ^a   Pollard, Patrick G ^a   Kalyani, Rubana N ^a   Tang, Rui ^a   MacNeil, Tanya ^a   Weinberg, David H ^a   Vongs, Aurawan ^a   Rosenblum, Charles I ^a   Doss, George A ^a   Miller, Randall R ^a   Stearns, Ralph A ^a   Peng, Qianping ^a   Tamvakopoulos, Constantin ^a   McGowan, Erin ^a   Martin, William J ^a   Metzger, Joseph M ^a   Shepherd, Cherrie A ^a   Strack, Alison M ^a   MacIntyre, D Euan ^a   Van Der Ploeg, Lex H T ^a   Patchett, Arthur A ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Melanocortin; Obesity; Sexual dysfunction

Indexed keywords

DEXFENFLURAMINE; HORMONE RECEPTOR STIMULATING AGENT; MB 243; MELANOCORTIN 4 RECEPTOR AGONIST; N [2 [4 CYCLOHEXYL 4 [[(1,1 DIMETHYLETHYL)AMINO]CARBONYL] 1 PIPERIDINYL] 1[(4 FLUOROPHENYL)METHYL] 2 OXOETHYL] 4 METHYL 2 PIPERAZINECARBOXAMIDE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; NONHUMAN; OBESITY; RAT; SUBSTITUTION REACTION;

ANIMALS; DOGS; HAPLORHINI; IMPOTENCE; MALE; MICE; OBESITY; PIPERAZINES; PIPERIDINES; RATS; RECEPTOR, MELANOCORTIN, TYPE 4;

EID: 9644307848     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.10.020     Document Type: Article

References (40)

1. For recent reviews on melanocortin system, see: W.J. Martin, and D.E. MacIntyre Eur. Urol. 45 2004 706
2. J.R. Holder, and C. Haskell-Luevano Med. Res. Rev. 24 2004 325
3. J. Voisey, L. Carroll, and A. van Daal Curr. Drug Targ. 4 2003 586
4. I. Sebhat, Z. Ye, M. Bednarek, D. Weinberg, R. Nargund, and T.M. Fong Annu. Rep. Med. Chem. 38 2003 31
5. I. Gantz, and T.M. Fong Am. J. Physiol. Endocrinol. Metab. 284 2003 E468
6. I.A. Zimanyi, and M.A. Pelleymounter Curr. Pharm. Des. 9 2003 1381
7. Y.K. Yang, and C.M. Harmon Obesity Rev. 4 2003 239
8. For rodent data, see: D. Lu, D. Willard, I.R. Patel, S. Kandell, L. Overton, T. Kost, M. Luther, W. Chen, R.P. Woychik, W.O. Wilkison, and R. Cone Nature 371 1994 799
9. D. Huszar, C.A. Lynch, V. Fair-Huntress, J.H. Dunmore, Q. Fang, L.R. Berkemeier, W. Gu, R.A. Kesterson, B.A. Boston, R.D. Cone, F.J. Smith, L.A. Campfield, P. Burn, and F. Lee Cell 88 1997 131
10. For human data, see: W. Gu, Z. Tu, P.W. Kleyn, A. Kissebath, L. Duprat, J. Lee, W. Chin, S. Maruti, N. Deng, S.L. Fisher, L.S. Franco, P. Burn, K.A. Yagaloff, J. Nathan, S. Heymsfield, J. Albu, F.X. Pi-Sunyer, and D.B. Allison Diabetes 48 1999 635
11. I.S. Farooqi, G.S. Yeo, J.M. Keogh, S. Aminian, S.A. Jebb, G. Butler, T. Cheetham, and S. O'Rahilly J. Clin. Invest. 106 2000 271
12. C. Lubrano-Berthelier, M. Cavazos, C. Le Stunff, K. Haas, S. Shapiro, S. Zhang, P. Bougneres, and C. Vaisse Diabetes 52 2003 2996
13. C. Lubrano-Berthelier, C. Le Stunff, P. Bougneres, and C. Vaisse J. Clin. Endocrinol. Metab. 89 2004 2028
14. For rodent data, see: H. Wessells Int. J. Imp. Res. 12 2000 S74
15. J.A. Lindia, R. Nargund, I. Sebhat, D. Weinberg, L.H.T. Van der Ploeg, D.E. MacIntyre, and W. Martin Int. J. Imp. Res. 13 2001 S55
16. L.H.T. Van der Ploeg, W.J. Martin, A.D. Howard, R.P. Nargund, C.P. Austin, X. Guan, J. Drisko, D. Cashen, I. Sebhat, A.A. Patchett, D.J. Figueroa, A.G. DiLella, D.H. Connolly, D.H. Weinberg, C.T. Tan, O.C. Palyha, S. Pong, T. MacNeil, C. Rosenblum, A. Vongs, R. Tang, H. Yu, A.W. Sailer, T.M. Fong, C. Huang, M. Tota, R.S. Chang, R. Stearns, C. Tamvakopoulos, G. Christ, D.L. Drazen, B.D. Spar, R.J. Nelson, and D.E. MacIntyre Proc. Natl. Acad. Sci. U.S.A. 99 2002 11381
17. W.J. Martin, E. McGowan, D.E. Cashen, L.T. Gantert, J.E. Drisko, G.J. Hom, R. Nargund, I. Sebhat, A.D. Howard, L.H.T. Van der Ploeg, and D.E. MacIntyre Eur. J. Pharmacol. 454 2002 71
18. For human data on non-subtype selective MCR agonists, see: H. Wessells, K. Fuciarelli, J. Hansen, M.E. Hadley, V.J. Hruby, R. Dorr, and N. Levine J. Urol. 160 1998 389
19. H. Wessells, D. Gralnek, R. Dorr, V.J. Hruby, M.E. Hadley, and N. Levine Urologia 56 2000 641
20. For recent patent reviews, see: M.A. Bednarek, and T.M. Fong Expert Opin. Ther. Patents 14 2004 1
21. J.D. Speak, and M.J. Bishop Expert Opin. Ther. Patents 12 2002 1631
22. J.E.S. Wikberg Expert Opin. Ther. Patents 11 2001 61
23. P.M. Anderson, A. Boman, E. Seifert, A. Skottner, and L. Torbjorn Expert Opin. Ther. Patents 11 2001 1583
24. B. Dyck, J. Parker, T. Phillips, L. Carter, B. Murphy, R. Summers, J. Hermann, T. Baker, M. Cismowski, J. Saunders, and V. Goodfellow Bioorg. Med. Chem. Lett. 13 2003 3793
25. T.I. Richardson, P.L. Ornstein, K. Briner, M.J. Fisher, R.T. Backer, C.K. Biggers, M.P. Clay, P.J. Emmerson, L.W. Hertel, H.M. Hsiung, S. Husain, S.D. Kahl, J.A. Lee, T.D. Lindstrom, M.J. Martinelli, J.P. Mayer, J.T. Mullaney, T.P. O'Brien, J.M. Pawlak, K.D. Revell, J. Shah, J.M. Zgombick, R.J. Herr, A. Melekhov, P.B. Sampson, and C.H.R. King J. Med. Chem. 47 2004 744
26. N. Xi, C. Hale, M.G. Kelly, M.H. Norman, M. Stec, S. Xu, J.W. Baumgartner, and C. Fotsch Bioorg. Med. Chem. Lett. 14 2004 377
27. R. Ruel, T.F. Herpin, L. Iben, G. Luo, A. Martel, H. Mason, G. Mattson, B. Poirier, E.H. Ruediger, D. Shi, C. Thibault, G. Yu, I.A. Zimanyi, G.S. Poindexter, and J.E. Macor Bioorg. Med. Chem. Lett. 13 2003 4341
28. F. Ujjainwalla, D. Warner, T.F. Walsh, M.J. Wyvratt, C. Zhou, L. Yang, R.N. Kalyani, T. MacNeil, L.H.T. Van der Ploeg, C.I. Rosenblum, R. Tang, A. Vongs, D.H. Weinberg, and M.T. Goulet Bioorg. Med. Chem. Lett. 13 2003 4431
29. Chu, D.; Boyce, R. S.; Duhl, D.; Chang, B. WO0218327, October 17, 2002
30. R.C. Rosen, L.E. Diamond, D.C. Earle, A.M. Shadiack, and P.B. Molinoff Int. J. Imp. Res. 16 2004 1
31. L.E. Diamond, D.C. Earle, R.C. Rosen, M.S. Willett, and P.B. Molinoff Int. J. Imp. Res. 16 2004 51
32. I.K. Sebhat, W.J. Martin, Z. Ye, K. Barakat, R.T. Mosley, D.B.R. Johnston, R. Bakshi, B. Palucki, D.H. Weinberg, T. MacNeil, R.N. Kalyani, R. Tang, R.A. Stearns, R.R. Miller, C. Tamvakopoulos, A.M. Strack, E. McGowan, D.E. Cashen, J.E. Drisko, G.J. Hom, A.D. Howard, D.E. MacIntyre, L.H.T. Van der Ploeg, A.A. Patchett, and R.P. Nargund J. Med. Chem. 45 2002 4589
33. Bakshi, R. K.; Hong, Q.; Olson, J. T.; Ye, Z.; Sebhat, I. K.; Barakat, K.; Pollard, P. G.; Weinberg, D. H.; MacNeil., T.; Kalyani, R. N.; Tank, R.; Martin, W. J.; Strack, A.; Cashen, D. E.; Drisko, J. E.; Horn, G. J.; Howard, A. D.; Tamvakopoulos, C.; Miller, R. R.; Stearns, R. A.; MacIntyre, D. E.; Van der Ploeg, L. H. T.; Patchett, A. A.; Nargund, R. P. Abstracts of Papers, 2, 25th National Meeting of the American Chemical Society, New Orleans, LA, March 23-27, 2003; American Chemical Society: Washington, DC, 2003
34. Ye, Z., et al. Unpublished results
35. For a detailed description of the assay protocols, see: M.A. Bednarek, T. MacNeil, R.N. Kalyani, R. Tang, L.H.T. Van der Ploeg, and D.H. Weinberg J. Med. Chem. 44 2001 3665
36. M.A. Bednarek, M.V. Siva, B. Arison, T. MacNeil, R.N. Kalyani, R.-R.C. Huang, and D.H. Weinberg Peptides 20 1999 401
37. Stearns, R. A., et al. Unpublished results
38. Strack, A. M., et al. Unpublished results
39. F. Giuliano, and J. Allard Int. J. Imp. Res. 14 2002 S53
40. Significant bioactivation was observed with MB243 in vitro to rat and human liver microsomal proteins, see: Doss, G. A.; Miller, R. R.; Zhang, Z.; Teffera, Y.; Nargund, R. P.; Palucki, B.; Park, M. K.; Tang, Y. S.; Evans, D. C.; Baillie, T. A.; Stearns, R. A. Chem. Res. Toxicol., submitted for publication