5240
J. Pontillo et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5237–5240
(b) Palucki, B. L.; Park, M. K.; Nargund, R. P.; Ye, Z.;
Sebat, 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.; Metz-
ger, J. M.; Shepherd, C. A.; Strack, A. M.; MacIntyre, E.;
Van der Ploeg, L. H. T.; Patchett, A. A. Bioorg. Med.
Chem. Lett. 2004, 15, 171.
significant difference between these two stereoisomers,
although the R-isomer 11i (Ki = 16 nM, EC50 = 33 nM,
IA = 96%) had a slightly better Emax value. Finally,
the homo-analogue of 11i exhibited comparable proper-
ties (11l, Ki = 16 nM, EC50 = 37 nM, IA = 96%) while its
isomeric tetraline 11k displayed 4-fold reduction in both
binding affinity and agonist potency. These detailed
SAR confirm the tetrahydroisoquinolinecarbonyl (Tic)
moiety is the optimal group at this region for several
known MC4R agonists such as 1.
3. Vos, T. J.; Caracoti, A.; Che, J.; Dai, M.; Farrer, C. A.;
Forsyth, N. E.; Drabic, S. V.; Horlick, R. A.; Lamppu, D.;
Yowe, D. L.; Balani, S.; Li, P.; Zeng, H.; Joseph, I. B. J.
K.; Rodriguez, L. E.; Claiborne, C. F. J. Med. Chem.
2004, 47, 1602, and references cited therein.
4. 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.; McGowan, 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.
5. Mutulis, F.; Yahorava, S.; Mutule, I.; Yahorau, A.;
Liepinsh, E.; Kopantshuk, S.; Veiksina, S.; Tars, K.;
Belyakov, S.; Mishnev, A.; Rinken, A.; Wikberg, J. E. S.
J. Med. Chem. 2004, 47, 4613.
6. An EC50 value is reported to be 80 nM for compound 1,5
which is significant different from the original reported
value by Sebhat et al. (2.1 nM)4 and by us (1.5 nM).9
7. Pontillo, J.; Tran, J. A.; Arellano, M.; Fleck, B. A.;
Huntley, R.; Marinkovic, D.; Lanier, M.; Nelson, J.;
Parker, J.; Saunders, J.; Tucci, F. C.; Jiang, W.; Chen, C.
W.; White, N. S.; Foster, A.; Chen, C. Bioorg. Med. Chem.
Lett. 2004, 14, 4417.
Receptor models of the human MC4 receptor12 indicate
that a cavity lined by several lipophilic amino acids and
two acidic residues (Asp122 and Asp126) of transmem-
brane-3 and -4 is unoccupied and could host a lipophilic
side chain with hydrogen-bonding ability from the cyclo-
hexane adjacent to the piperazine in 2a.9 Interestingly, the
Tic-group, which is important for receptor activation,
resides in an area near transmembrane-3, -4, and -5 based
on this model, and the basic nitrogen of the Tic-group
most likely interacts with the acidic residue Asp126 of
the receptor. Further studies are required to understand
the interaction of key residues of the MC4R with the
lipophilic part of this Tic group.
In conclusion, a series of cyclohexylpiperazines bearing
an amide side chain was synthesized and studied as
ligands of the melanocortin-4 receptor. Compounds
with an additional phenylacetamido group displayed im-
proved potency in both binding and activation over 2a
or b. Structure–activity relationship studies revealed that
the Tic-group is very important for receptor activation.
Compound 11i (EC50 = 33 nM, IA = 96%) was identi-
fied as a potent agonist of MC4R.
8. Chen, C.; Pontillo, J.; Fleck, B. A.; Gao, Y.; Wen, J.;
Tran, J. A.; Tucci, F. C.; Marinkovic, D.; Foster, A. C.;
Saunders, J. J. Med. Chem. 2004, 47, 6821.
9. Tran, J. A.; Pontillo, J.; Arellano, M.; Fleck, B. A.;
Tucci, F. C.; Marinkovic, D.; Chen, W. C.; Saunders, J.;
Foster, A. C.; Chen, C. Bioorg. Med. Chem. Lett. 2005,
15, 3434.
References and notes
10. Nickolls, S. A.; Cismowski, M. I.; Wang, X.; Wolff, M.;
Conlon, P. J.; Maki, R. A. J. Pharmacol. Exp. Ther. 2003,
304, 1217.
1. Goodfellow, V.; Saunders, J. Curr. Med. Chem. 2003, 3,
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11. Tran, J.; Pontillo, J.; Arellano, M.; White, N. S.; Fleck, B.
A.; Marinkovic, D.; Tucci, F. C.; Lanier, M.; Nelson, J.;
Saunders, J.; Foster, A. C.; Chen, C. Bioorg. Med. Chem.
Lett. 2005, 15, 833.
12. Wilczynski, A.; Wang, X. S.; Joseph, C. G.; Xiang, Z.;
Bauzo, R. M.; Scott, J. W.; Sorensen, N. B.; Shaw, A. M.;
Millard, W. J.; Richards, N. G.; Haskell-Luevano, C.
J. Med. Chem. 2004, 47, 2194.
2. (a) Richardson, T. I.; Ornstein, P. L.; Briner, K.; Fisher,
M. J.; Backer, R. T.; Biggers, C. K.; Clay, M. P.;
Emmerson, P. J.; Hertel, L. W.; Hsiung, H. M.; Husain,
S.; Kahl, S. D.; Lee, J. A.; Lindstrom, T. D.; Martinelli,
M. J.; Mayer, J. P.; Mullaney, J. T.; OÕBrien, T. P.;
Pawlak, J. M.; Revell, K. D.; Shah, J.; Zgombick, J. M.;
Herr, R. J.; Melekhov, A.; Sampson, P. B.; King, C.-H. R.
J. Med. Chem. 2004, 47, 744, and references cited therein;