Discovery of highly potent and efficacious MC4R agonists with spiroindane N-Me-1,2,4-triazole privileged structures for the treatment of obesity

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 22, 2010, Pages 6524-6532

  He, Shuwen ^a   Ye, Zhixiong ^a   Dobbelaar, Peter H ^a   Bakshi, Raman K ^a   Hong, Qingmei ^a   Dellureficio, James P ^a   Sebhat, Iyassu K ^a   Guo, Liangqin ^a   Liu, Jian ^a   Jian, Tianying ^a   Lai, Yingjie ^a   Franklin, Christopher L ^a   Reibarkh, Mikhail ^a   Holmes, Mark A ^a   Weinberg, David H ^a   MacNeil, Tanya ^a   Tang, Rui ^a   Tamvakopoulos, Constantin ^a   Peng, Qianping ^a   Miller, Randy R ^a   Stearns, Ralph A ^a   Chen, Howard Y ^a   Chen, Airu S ^a   Strack, Alison M ^a   Fong, Tung M ^a   Wyvratt Jr , Matthew J ^a   Nargund, Ravi P ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Agonist; MC4R; Melanocortin subtype 4 receptor; Obesity; Privileged structure; Spiroindane; Triazole

Indexed keywords

1,2,4 TRIAZOLE DERIVATIVE; ANTIOBESITY AGENT; INDAN DERIVATIVE; MELANOCORTIN 4 RECEPTOR; MELANOCORTIN RECEPTOR AGONIST; MK 0489; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; AREA UNDER THE CURVE; ARTICLE; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG STRUCTURE; MOUSE; NONHUMAN; OBESITY; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; DISEASE MODELS, ANIMAL; MICE; MICE, KNOCKOUT; MOLECULAR STRUCTURE; OBESITY; RATS; RECEPTOR, MELANOCORTIN, TYPE 4; STRUCTURE-ACTIVITY RELATIONSHIP; TRIAZOLES;

RODENTIA;

EID: 77958041827     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.09.049     Document Type: Article

References (39)

1. R.D. Cone Endocr. Rev. 27 2006 736
2. I. Gantz, and T.M. Fong Am. J. Physiol. Endocrinol. Metab. 284 2003 E468
3. Y.K. Yang, and C.M. Harmon Obes. Rev. 4 2003 239
4. Y.-X. Tao Endocr. Rev. 31 2010 506
5. D. Huszar, C.A. Lynch, V. Fairchild-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
6. C. Vaisse, K. Clement, B. Guy-Grand, and P. Froguel Nat. Genet. 20 1998 113
7. G.S. Yeo, I.S. Farooqi, S. Aminian, D.J. Halsall, R.G. Stanhope, and S. O'Rahilly Nat. Genet. 20 1998 111
8. For the original description of agouti gene see: Woychik, R. P. US 6,080,550, June 27, 2000.
9. R.P. Nargund, A.M. Strack, and T.M. Fong J. Med. Chem. 49 2006 4035
10. F. Ujjainwalla, and I.K. Sebhat Curr. Top. Med. Chem. 7 2007 1068
11. 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
12. B.L. Palucki, M.K. Park, R.P. Nargund, Z. Ye, I.K. Sebhat, P.G. Pollard, R.N. Kalyani, R. Tang, T. MacNeil, D.H. Weinberg, A. Vongs, C.I. Rosenblum, G.A. Doss, R.R. Miller, R.A. Stearns, Q. Peng, C. Tamvakopoulos, E. McGowan, W.J. Martin, J.M. Metzger, C.A. Shepherd, A.M. Strack, D.E. MacIntyre, L.H.T. Van der Ploeg, and A.A. Patchett Bioorg. Med. Chem. Lett. 15 2005 171
13. F. Ujjainwalla, D. Warner, C. Snedden, R.D. Grisson, T.F. Walsh, M.J. Wyvratt, R.N. Kalyani, T. MacNeil, R. Tang, D.H. Weinberg, L.H.T. van der Ploeg, and M.T. Goulet Bioorg. Med. Chem. Lett. 15 2005 4023
14. Ujjainwalla, F. Abstracts of Papers, Presentation (MEDI-275), 230th ACS National Meeting, Washington, DC, Aug 28-Sept 1, 2005.
15. L. Guo, Z. Ye, F. Ujjainwalla, H. Sings, I.K. Sebhat, J. Huber, D.H. Weinberg, R. Tang, T. McNeil, C. Tamvakopoulos, Q. Peng, E. MacIntyre, L.H.T. van der Ploeg, M.T. Goulet, M.J. Wyvratt, and R.P. Nargund Bioorg. Med. Chem. Lett. 18 2008 3242
16. S. He, Z. Ye, P.H. Dobbelaar, I.K. Sebhat, L. Guo, J. Liu, T. Jian, Y. Lai, C.L. Franklin, R.K. Bakshi, J.P. Dellureficio, Q. Hong, N.N. Tsou, R.G. Ball, D.E. Cashen, W.J. Martin, D.H. Weinberg, T. MacNeil, R. Tang, C. Tamvakopoulos, Q. Peng, R.R. Miller, R.A. Stearns, H.Y. Chen, A.S. Chen, A.M. Strack, T.M. Fong, D.E. MacIntyre, M.J. Wyvratt, and R.P. Nargund Bioorg. Med. Chem. Lett. 20 2010 2106
17. S. He, Z. Ye, P.H. Dobbelaar, I.K. Sebhat, L. Guo, J. Liu, T. Jian, Y. Lai, C.L. Franklin, R.K. Bakshi, J.P. Dellureficio, Q. Hong, D.H. Weinberg, T. MacNeil, R. Tang, C. Tamvakopoulos, Q. Peng, R.R. Miller, R.A. Stearns, H.Y. Chen, A.S. Chen, A.M. Strack, T.M. Fong, M.J. Wyvratt, and R.P. Nargund Bioorg. Med. Chem. Lett. 20 2010 4399
18. X. Tian, A.G. Switzer, S.A. Derose, R.K. Mishra, M.G. Solinsky, R.N. Mumin, F.H. Ebetino, L.R. Jayasinghe, M.E. Webster, A.-O. Colson, D. Crossdoersen, B.B. Pinney, J.A. Farmer, M.E. Dowty, C.M. Obringer, C.A. Cruze, M.L. Burklow, P.M. Suchanek, L. Dong, M.K. Dirr, R.J. Sheldon, and J.A. Wos J. Med. Chem. 51 2008 6055
19. X.W. Liu, J. Ma, A.-O. Colson, D.C. Doersen, and F.H. Ebetino Bioorg. Med. Chem. Lett. 18 2008 1223
20. C. Chen Prog. Med. Chem. 45 2007 111
21. C. Chen, W. Jiang, J.A. Tran, F.C. Tucci, B.A. Fleck, S. Markison, J. Wen, A. Madan, S.R. Hoare, A.C. Foster, D. Marinkovic, C.W. Chen, M. Arellano, and J. Saunders Bioorg. Med. Chem. Lett. 18 2008 129
22. W. Jiang, J.A. Tran, F.C. Tucci, B.A. Fleck, S.R. Hoare, S. Markison, J. Wen, C.W. Chen, D. Marinkovic, M. Arellano, A.C. Foster, and C. Chen Bioorg. Med. Chem. Lett. 17 2007 6546
23. C.G. Joseph, K.R. Wilson, M.S. Wood, N.B. Sorenson, D.V. Phan, Z. Xiang, R.M. Witek, and C. Haskell-Luevano J. Med. Chem. 51 2008 1423
24. S.L. Kuklish, R.T. Backer, K. Briner, C.W. Doecke, S. Husain, J.T. Mullaney, P.L. Ornstein, J.M. Zgombick, T.P. O'Brien, and M.F. Fisher Bioorg. Med. Chem. Lett. 16 2006 3843
25. Attempt to remove Boc group under routine conditions (e.g., 4 M HCl in dioxane) was unsuccessful probably due to the instability of the oxadiazole moiety. For Boc deprotection using ceric ammonium nitrate (CAN), see: J.R. Hwu, M.L. Jain, S.-C. Tsay, and G.H. Hakimelahi Tetrahedron Lett. 37 1996 2035
26. The configurations of 5d1 and 5d2 were not firmly established. However, based on the potency on MC4R (Table 1), 5d1 likely has R configuration on spiroindane while 5d2 has S configuration.
27. A.S.K. Hashmi, J.P. Weyrauch, W. Frey, and J.W. Bats Org. Lett. 6 2004 4391
28. The structure of privileged structure 24 was established by NMR studies. See the Supplementary data.
29. All data are mean values for at least three separate experiments. For a detailed description of the assay protocols, see:
30. 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
31. 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
32. 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
33. For a discussion of MC4R/3R double knockout mouse, see: A.S. Chen, D.J. Marsh, M.E. Trumbauer, E.G. Frazier, X.-M. Guan, H. Yu, C.I. Rosenblum, A. Vongs, Y. Feng, L. Cao, J.M. Metzger, A.M. Strack, R.E. Camacho, T.N. Mellin, C.N. Nunes, W. Min, J. Fisher, S. Gopal-Truter, D.E. MacIntyre, H.Y. Chen, and L.H.T. Van der Ploeg Nat. Genet. 26 2000 97
34. Ujjainwalla, F.; Young, J. R., manuscript in preparations.
35. C. Regan, C. Shepherd, A. Strack, D. Weinberg, R. Nargund, Z. Ye, P. Pollard, T. Fong, I. Reynolds, and J. Lynch Pharmacology 83 2009 38
36. Hong, Q.; Bakshi, R. K. et al., manuscript in preparations.
37. S. Kim, J.I. Lee, and Y.C. Kim J. Org. Chem. 50 1985 560
38. Compound A was discovered previously in our laboratories. Ujjainwalla, F; Sings, H. L. unpublished results.
39. 50 0.052 nM, 117% act.). Its potency on murine MC3R was not determined. If we assume the potency is similar to the data on human MC3R, the possible involvement of MC3R in the efficacy observed can not be ruled out completely, although analog 32 is over 100-fold more potent on MC4R than MC3R.