1242
J. A. Jablonowski et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1239–1242
Table 7. Representative combination analogues and their binding
affinity to the NPY Y2 receptor
References and notes
1. Kaga, T.; Fujimiya, M.; Inui, A. Peptides 2001, 22, 501.
2. Blomqvist, A. G.; Herzog, H. Trends Neurosci. 1997, 20,
294.
3. Michel, M. C.; Beck-Sickinger, A.; Cox, H.; Doods, H. N.;
Herzog, H.; Larhammar, D.; Quirion, R.; Schwartz, T.;
Westfall, T. Pharmacol. Rev. 1998, 50, 143.
4. Parker, E.; Van Heck, M.; Stamford, A. Eur. J. Pharma-
col. 2002, 440, 173.
5. Naveilhan, P.; Hassani, H.; Canals, J. M.; Ekstrand, A. J.;
Larefalk, A.; Chhajlani, V.; Arenas, E.; Gedda, K.;
Svensson, L.; Thoren, P.; Ernfors, P. Nat. Med. 1999, 5,
1188.
6. Batterham, R. L.; Cowley, M. A.; Small, C. J.; Herzog,
H.; Cohen, M. A.; Dakin, C. L.; Wren, A. M.; Brynes,
A. E.; Low, M. J.; Ghatel, M. A.; Cone, R. D.; Bloom,
S. R. Nature 2002, 418, 650.
No.
R=
X=
Binding affinity15
IC50, mM
56
57
58
59
60
C6H11(CH2)2
C6H11(CH2)2
C5H9(CH2)2
C5H9(CH2)2
C5H9(CH2)2
4-Cl
3-NO2
4-Cl
3-NO2
3-CN
1.1ꢁ0.1
0.5ꢁ0.09
1.1ꢁ0.1
0.35ꢁ0.05
0.1ꢁ0.01
7. Sainsbury, A.; Schwartzer, C.; Couzens, M.; Fetissov, S.;
Furtinger, S.; Jenkins, A.; Cox, H. M.; Sperk, G.; Hok-
felt, T.; Herzog, H. Proc. Natl. Acad. Sci. U.S.A. 2002, 99,
8938.
8. Baldock, P. A.; Sainsbury, A.; Couzens, M.; Enriquez,
R. F.; Thomas, G. P.; Gradiner, E. M.; Herzog, H. J.
Clin. Invest. 2002, 109, 915.
9. Herzog, H. Drug News Perspect. 2002, 15, 506.
10. Grouzmann, E.; Buclin, T.; Martire, M.; Cannizzaro, C.;
Dorner, B.; Razaname, A.; Mutter, M. J. Biol. Chem.
1997, 272, 7699.
Conversely, the cyclopentylethyl analogues 58–60 dis-
played a wide range of activities. No change in activity
was seen with the 4-Cl cinnamide 58 and a slight
increase in activity was observed in the 3-NO2 cinna-
mide substituted analogue, 59. However, the 3-CN cin-
namide analogue (60) showed a marked increase in
binding activity at IC50=0.1 mM. Through combining
the optimal substitution on the indoline, the cinnamide
and the piperidine, we prepared the most potent
analogue, 60.
11. Doods, H.; Gaida, W.; Wieland, H. A.; Dollinger, H.;
Schnorrenberg, G.; Esser, F.; Engel, W.; Eberlein, W.;
Rudolf, K. Eur. J. Pharmacol. 1999, 384, R3.
12. Bonaventure, P.; Nepomuceno, D.; Mazur, C.; Lord, B.;
Rudolph, D. A.; Jablonowski, J. A.; Carruthers, N. I.;
Lovenberg, T. W. J. Pharmacol. Exp. Ther. 2004, in press.
13. All compounds presented in this paper were characterized
A detailed biological evaluation of compound 60, also
known as JNJ-5207787, was undertaken due to its high
affinity forthe NPY Y
receptor. JNJ-5207787 was
2
demonstrated to be an antagonist via inhibition of PYY-
stimulated [35S]GTPgS binding (pIC50 corr=7.2ꢁ0.12).12
This compound was also found to be >100-fold selec-
tive versus human Y1, Y4 and Y5 receptors as evaluated
by radioligand binding.12 In addition, JNJ-5207787 was
found to be selective against a wide variety of receptors
and enzymes (inhibition <50% at 1 mM).
1
by H NMR and MS.
14. Kitagawa, T.; Arita, J.; Nagahata, A. Chem. Pharm. Bull.
1994, 42, 1655.
15. IC50 values are the mean of two to six determinations12
(unless noted otherwise) followed by the SEM, given in
parentheses.
16. Karp, G. M.; Condon, M. E. J. Heterocycl. Chem. 1994,
31, 1513.
17. Bouzard, D.; DiCesare, P.; Essiz, M.; Jacquet, J. P.;
Ledoussal, B.; Remuzon, P.; Kessler, R. E.; Fung-Tomc,
J. J. Med. Chem. 1992, 35, 518.
18. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
19. During the preparation of the current manuscript, the first
description of small molecule NPY Y2 ligands appeared
without comment on theirfunctional activity. Anders,
C. J.; Zimanyi, I. A.; Deshpande, M. S.; Iben, L. G.;
Grant-Young, K.; Mattson, G. K.; Zhai, W. Bioorg. Med.
Chem. Lett. 2003, 13, 2883.
In conclusion, through an HTS effort a series of indo-
lylpiperidines, exemplified by 1 were identified as
potential NPY Y2 ligands. Through a medicinal chem-
istry program, we prepared compounds with 40-fold
higheraffinity forthe erceptor(
60, JNJ-5207787,
IC50=0.1 mM). Further biological evaluation of this
compound determined that it behaved as a selective
NPY Y2 antagonist. Thus, we have identified the first
small molecule NPY Y2 antagonist.19