Design and syntheses of melanocortin subtype-4 receptor agonists. Part 2: Discovery of the dihydropyridazinone motif

Bioorganic and Medicinal Chemistry Letters

Volumn 15, Issue 18, 2005, Pages 4023-4028

  Ujjainwalla, Feroze ^a   Warner, Daniel ^a   Snedden, Christine ^a   Grisson, Ricky D ^a   Walsh, Thomas F ^a   Wyvratt, Matthew J ^a   Kalyani, Rubana N ^a   MacNeil, Tanya ^a   Tang, Rui ^a   Weinberg, David H ^a   Van Der Ploeg, Lex ^b   Goulet, Mark T ^b  

^a MERCK RESEARCH LABORATORIES   (United States)

^b Merck Research Laboratories Boston   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIOBESITY AGENT; MELANOCORTIN 4 RECEPTOR; MELANOCORTIN 4 RECEPTOR AGONIST; PYRIDAZINONE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; DRUG ACTIVITY; DRUG DESIGN; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS;

DRUG DESIGN; HUMANS; INHIBITORY CONCENTRATION 50; MOLECULAR STRUCTURE; PYRIDAZINES; RECEPTOR, MELANOCORTIN, TYPE 4; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 23644458900     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.06.033     Document Type: Article

References (29)

1. For recent reviews on the Melanocortin system see I.A. Zimanyi, and M.A. Pelleymounter Curr. Pharm. Des. 9 2003 627
2. I. Gantz, and T.M. Fong Am. J. Physiol. Endocrinol. Metab. 284 2003 E468
3. D.J. MacNeil, A.D. Howard, X. Guan, T.M. Fong, R. Nargund, M.A. Bednarek, M.T. Goulet, D.H. Weinberg, A.M. Strack, D.J. Marsh, H.Y. Chen, C.-P. Shen, A.S. Chen, C.I. Rosenblum, T. MacNeil, M. Tota, D.E. MacIntyre, and L.H.T. Van der Ploeg Eur. J. Pharmacol. 440 2002 141
4. J.E.S. Wikberg Exp. Opin. Ther. Patents 11 2001 61
5. P.M. Anderson, A. Boman, E. Seifert, A. Skottner, and T. Lundstedt Exp. Opin. Ther. Patents 11 2001 1583
6. J.E.S. Wikberg Eur. J. Pharmacol. 375 1999 295
7. 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
8. A. Hinney, A. Schmidt, K. Nottebom, O. Heibult, I. Becker, A. Ziegler, G. Gerber, M. Sina, T. Gorg, H. Mayer, W. Siegfried, M. Fichter, H. Remschmidt, and J. Hebebrand J. Clin. Endocrinol. Metab. 84 1999 1483
9. W. Gu, Z. Tu, P.W. Kleyn, A. Kissebah, 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
10. R.D. Cone Trends Endocrinol. Metab. 10 1999 211
11. 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
12. C. Fotsch, D.M. Smith, J.A. Adams, J. Cheetham, M. Croghan, E.M. Doherty, C. Hale, M.A. Jarosinski, M.G. Kelly, M.H. Norman, N.A. Tamayo, N. Xi, and J.W. Baumgartner Bioorg. Med. Chem. Lett. 13 2003 2337
13. I.K. Sebhat, W.J. Martin, Y. Zhixiong, 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. Miller, C. Tamvakopoulos, A. Strack, E. McGowan, D.E. Cashen, J.E. Drisko, G.J. Horn, 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
14. J.D. Speake, and M.J. Bishop Exp. Opin. Ther. Patents 12 2002 1631
15. 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. Weinberg, and M.T. Goulet Bioorg. Med. Chem. Lett. 13 2003 4431
16. N. Miyaura, and A. Suzuki Chem. Rev. 95 1995 2457
17. J.A. Profitt, D.S. Watt, and E.J. Corey J. Org. Chem. 40 1975 127
18. T. Hudlicky, G. Sinai-Zingde, and M.G. Natchus Tetrahedron Lett. 28 1987 5287
19. A. Padwa, and W. Dent J. Org. Chem. 52 1987 235
20. Y. Terao, H. Kotaki, N. Imai, and K. Achiwa Chem. Pharm. Bull. 33 1985 2762
21. D.M.T. Chan, K.L. Monaco, R.P. Wang, and M.P. Winters Tetrahedron Lett. 39 1998 2933
22. D.A. Evans, J.L. Katz, and T.R. West Tetrahedron Lett. 39 1998 2937
23. G.R. Brown, A.J. Foubister, and B. Wright J. Chem. Soc. Chem. Commun. 1984 1373
24. 50 is defined as the inflection point of the cAMP dose-response curve for any given compound. %Max is the percentage of cAMP accumulation at 10 μM of compound relative to α-MSH. 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
25. M.A. Bednarek, M.V. Silva, B. Arison, T. MacNeil, R.N. Kalyani, R.-R.C. Huang, and D.H. Weinberg Peptides 20 1999 401
26. All compounds are single enantiomers, >95% pure (HPLC) and were tested as either TFA or HCl salts.
27. B of 3.1 ± 0.64 nM was calculated from Schild analysis.
28. T. Fukuyama, C.-K. Jow, and M. Cheung Tetrahedron Lett. 36 1995 6373
29. C.P. Tan, K.K. McKee, D.H. Weinberg, T. MacNeil, O.C. Palyha, S.D. Feighner, D.L. Hreniuk, L.H.T. Van Der Ploeg, D.J. MacNeil, and A.D. Howard FEBS Lett. 451 1999 137