F. Ujjainwalla et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4023–4028
4027
Table 7. Binding affinity and functional activity of compounds at the
human MC4R10,11
Table 8. Human MCR activity profile of 26, 63, and 6710,11
Compound Receptor Binding IC50 cAMP EC50
(nM)
(nM) (%max)
12 7% at 10 lM
2% at 10 lM
40 7.0 (67 2%)
2400 390 (27 2%)
220 41 (33 8%)
1100 280 (21 3%)
30 5.2 (98 3%)
26
63
67
MC1B14
MC3
MC4
230 0.0
420 47
1.5 0.2
5
MC5
1100 140
1100 64
4700 92
22 2.8
MC1B14
MC3
MC4
Compound C-4 stereo Ra,b
Binding cAMP EC50
IC50 (nM) (nM) (%max)
MC5
3100 290
290 93
7
2% at 10 lM
MC1B14
MC3
MC4
240 31 (18 2%)
10 2% at 10 lM
66 19 (90 3%)
1600 1000
18 3.6
690 132
25
26
60
R or S
S or R
R or S
26
390 (72%)
40 (67%)
MC5
5
1% at 10 lM
References and notes
1.5
1. (a) For recent reviews on the Melanocortin system see
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Kissebah, A.; Duprat, L.; Lee, J.; Chin, W.; Maruti, S.;
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3. (a) Dyck, B.; Parker, J.; Phillips, T.; Carter, L.; Murphy,
B.; Summers, R.; Hermann, J.; Baker, T.; Cismowski, M.;
Saunders, J.; Goodfellow, V. Bioorg. Med. Chem. Lett.
2003, 13, 3793; (b) Fotsch, C.; Smith, D. M.; Adams, J. A.;
Cheetham, J.; Croghan, M.; Doherty, E. M.; Hale, C.;
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Lett. 2003, 13, 2337; (c) Sebhat, I. K.; Martin, W. J.;
Zhixiong, Y.; Barakat, K.; Mosley, R. T.; Johnston, D. B.
R.; Bakshi, R.; Palucki, B.; Weinberg, D. H.; MacNeil, T.;
Kalyani, R. N.; Tang, R.; Stearns, R. A.; Miller, R.;
Tamvakopoulos, C.; Strack, A.; McGowan, E.; Cashen,
D. E.; Drisko, J. E.; Horn, G. J.; Howard, A. D.;
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1631.
560
20% at 10 lM
61
62
63
64
65
66
67
68
69
S or R
R or S
S or R
R or S
S or R
R or S
S or R
R or S
S or R
690
540
22
4000 (32%)
480 (100%)
30 (98%)
1300
280
47
2000 (16%)
1400 (33%)
1200 (90%)
66 (98%)
18
780
430
4000 (26%)
740 (48%)
a Absolute stereochemistry.
b Ar signifies 4-fluorophenyl.
4. Ujjainwalla, F.; Warner, D.; Walsh, T. F.; Wyvratt, M. J.;
Zhou, C.; Yang, L.; Kalyani, R. N.; MacNeil, T.; Van der
Ploeg, L. H. T.; Rosenblum, C. I.; Tang, R.; Vongs, A.;
Weinberg, D.; Goulet, M. T. Bioorg. Med. Chem. Lett.
2003, 13, 4431.
agonists derived from a dihydropyridazinone architec-
ture. This SAR study has transformed the MC4R ago-
nists 1, 2, and 3 to the more potent and subtype
selective agonists 26, 63, and 67, respectively.
5. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.