I. K. Sebhat et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5720–5723
5723
Table 2. Binding and functional activity of compounds 11a–11z at human melanocortin receptors
Compound
MC4R (IC50, nM)a
EC50 (nM)a [% max]
MC4R
MC3R
MC5R
11a
11b
11c
11d
11e
11f
11g
11h
11i
13.6 ( 4)
840 ( 149)
177 ( 13)
6.8 ( 1)
6.5 ( 1) [98]
na [14]
na [2]
na [4]
977 ( 123) [31]
na [5]
na [8]
2174 ( 732) [54]
563 ( 146) [55]
10.0 ( 4) [81]
546 ( 312) [87]
151 ( 54) [55]
57.8 ( 26) [79]
84.6 ( 15) [76]
1769 ( 725) [59]
230 ( 58) [37]
241 ( 76) [42]
na [2]
888 ( 93) [27]
1117 ( 95) [19]
na [32]
162 ( 81)
66.2 ( 16)
36.6 ( 9)
64.0 ( 6)
343 ( 98)
na [5]
na [8]
na [3]
1980 ( 186) [56]
na [12]
na [2]
a Values are means of at least three experiments, standard error of the mean is given in parentheses (na, not active).
Fairhurst, A. M.; Van der Ploeg, L. H. T.; MacIntyre, D.
E.; Mellin, T. N. Neuropeptides 1998, 32, 491; (h) Giraudo,
S. Q.; Billington, C. J.; Levine, A. S. Brain Res. 1998, 809,
302; (i) Kask, A.; Rago, L.; Korrovits, P.; Wikberg, J. E. S.;
Schiotch, H. B. Biochem. Biophy. Res. Commun. 1998, 248,
245.
The most potent compounds in the first two series had
maintained either a cyclohexane, sec-butyl or iso-butyl
substituent. The amide series (11) allowed us to investi-
gate further substitutions about these core-structures.
While unsaturation (11h), substitution of the branch
point (11f and 11g), 4,4-di-substitution (11e) or cycliza-
tion (11b and 11c) all reduced potency compared to their
respective parents, 4-position mono-methylation (11d)
maintained very similar activity (see Table 2).
3. Huszar, D.; Lynch, C. A.; Fairchild-Huntress, V.; Dun-
more, J. H.; Fang, Q.; Berkemeier, L. R.; Gu, W.;
Kesterson, R. A.; Boston, B. A.; Cone, R. D.; Smith, F.
J.; Campfield, L. A.; Burn, P.; Lee, F. Cell 1997, 88,
131.
4. For a recent review, see: Nargund, R. P.; Strack, A. M.;
Fong, T. M. J. Med. Chem. 2006, 49, 4035; (a) Sebhat, I.
K.; Martin, W. J.; Ye, Z.; 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. R.; Tamvakopoulos, C.; Strack, A. M.; McGo-
wan, E.; Cashen, D. E.; Drisko, J. E.; Hom, G. J.; Howard,
A. D.; MacIntyre, D. E.; Van der Ploeg, L. H. T.; Patchett,
A. A.; Nargund, R. P. J. Med. Chem. 2002, 45, 4589; Van
der (b) Ploeg, L. H. T.; Martin, W. J.; Howard, A. D.;
Nargund, R. P.; Austin, C. P.; Guan, X.; Drisko, J.;
Cashen, D.; Sebhat, I.; Patchett, A. A.; Figueroa, D. J.;
DiLella, A. G.; Connolly, D. H.; Weinberg, D. H.; Tan, C.
T.; Palyha, O. C.; Pong, S.; MacNeil, T.; Rosenblum, C.;
Vongs, A.; Tang, R.; Yu, H.; Sailer, A. W.; Fong, T. M.;
Huang, C.; Tota, M.; Chang, R. S.; Stearns, R.; Tamvak-
opoulos, C.; Christ, G.; Drazen, D. L.; Spar, B. D.; Nelson,
R. J.; MacIntyre, D. E. Proc. Natl. Acad. Sci. U.S.A. 2002,
99, 11381; (c) Cashen, Doreen E.; MacIntyre, D. Euan;
Martin, Willian J. Br. J. Pharmacol. 2002, 136; (d) Palucki,
B. L.; Park, M. K.; Nargund, R. P.; Ye, Z.; Sebhat, I. K.;
Pollard, P. G.; Kalyani, R. N.; Tang, R.; MacNeil, T.;
Weinberg, D. H.; Vongs, A.; Rosenblum, C. I.; Doss, G.
A.; Miller, R. R.; Stearns, R. A.; Peng, Q.; Tamvakopoulos,
C.; McGowan, E.; Martin, W. J.; Metzger, J. M.; Shepherd,
C. A.; Strack, A. M.; MacIntyre, D. E.; Van der Ploeg, L.
H. T.; Patchett, A. A. Bioorg. Med. Chem. Lett. 2005, 15,
171.
In conclusion, the three sets of MC4 receptor agonists
(nitriles, tetrazoles, and amides) allowed us to identify
suitable alkyl substituents of the piperidine core in this
lead series. The low potency of compounds bearing
small alkyl groups suggests that this region of the mole-
cule interacts with a large lipophilic pocket in the hMC4
receptor. A number of larger groups, in particular cyclo-
pentyl, n-butyl, neo-pentyl, iso-butyl, sec-butyl, and
cyclohexyl derivatives, furnished compounds with good
potency at hMC4R. This variety of substituents may
prove useful in tempering the in vivo and physical char-
acteristics of the lead series.
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