1046
C. P. Leslie et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1043–1046
Table 3. Structure–activity relationship of the amide group
Pickel, V. M.; Dimaggio, D. A.; Hotchkiss, A. J.; Crowly,
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O
R1R2N
4. Stanley, B. G.; Leibowitz, S. F. Proc. Natl. Acad. Sci.
U.S.A 1985, 82, 3940.
5. Boublik, J. H.; Scott, N. A.; Brown, M. R.; Rivier, J. E.
J. Med. Chem. 1989, 32, 597.
N
O
NH
F
Cl
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7. Rudolf, K.; Eberlein, W.; Engel, W.; Wieland, H. A.;
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R11.
Compound
NR1 R2
NPY Y1
binding
affinity
Calculated
pKa for NR1R2
IC50 (nM)
14
53
8.3
N
N
8. Serradeil-Le Gal, C.; Valette, G.; Rouby, P.-E.; Pellet, A.;
Oury-Donat, F.; Brossard, G.; Lepsy, L.; Marty, E.;
Neliat, G.; Conite, P.; Maffrand, J.-P.; Le Fur, G. FEBS
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10. Hipskind, P. A.; Lodd, K. L.; Nixon, J. A.; Britton, T. C.;
Bruns, R. F.; Catlow, J.; Dieckman-McGinty, D. K.;
Gackenheimer, S. L.; Gitter, B. D.; Iyengar, S.; Schober,
D. A.; Simmons, R. M. A.; Swanson, S.; Zarrinmayeh, H.;
Zimmerman, D. M.; Gehlert, D. R. J. Med. Chem. 1997,
40, 3712.
11. Kanatani, A.; Hata, M.; Mashiko, S.; Ishihara, A.;
Okamoto, O.; Haga, Y.; Ohe, T.; Kanno, T.; Murai, N.;
Ishii, Y.; Fukuroda, T.; Fukami, T.; Ihara, M. Mol.
Pharmacol. 2001, 59, 501.
12. Di Fabio, R.; Giovannini, R.; Bertani, B.; Borriello, M.;
Bozzoli, A.; Donati, D.; Falchi, A.; Ghirlanda, D.; Leslie,
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Med. Chem. Lett. 2006, 16, 1749.
N
26
27
28
29
30
31
32
871
467
8.2
9.0
8.9
9.0
9.0
10.3
—
N
N
N
N
50
N
H
N
191
N
N
H
263
N
1862
12022
N
N
H
13. Unpublished results, GSK.
14. pKa’s were calculated using ACD/Labs software (http://
between the axial and equatorial fluoropiperidine isomers,
pKa’s for compounds 12, 13, 14, 15 and 17 were calculated
by correcting the values for the corresponding non-
fluorinated piperidines according to van Niel, M. B.;
Collins, I.; Beer, M.S.; Broughton, H. B.; Cheng, S. K. F.;
Goodacre, S. C.; Heald, A.; Locker, K. L.; MacLeod, A.
M.; Morrison, D.; Moyes, C. R.; O’Connor, D.; Pike, A.;
Rowley, M.; Russel, N.; Sohal, B.; Stanton, J. A.;
Thomas, S.; Verrier, H.; Watt, A. P.; Castro, J. L.
J. Med. Chem. 1999, 42, 2087 (À1.83 pKa units for an axial
fluorosubstituent and À3.24 pKa units for an equatorial
fluorosubstituent). The authors believe that the calculated
pKa for compound 17 may be an overestimation as
experimentally determined pKa values of cyclopropanated
amines can show a 2 pKa unit drop compared to the non-
alkylated amines (for example, see Gillaspy, M. L.; Lefker,
B. A.; Hada, W. A.; Hoover, D. J. Tetrahedron Lett. 1995,
41, 7399).
N
Acknowledgments
The authors thank the Computational, Analytical and
Structural Sciences group, the In Vitro Pharmacology
and the DMPK laboratories of GlaxoSmithkline SpA,
Verona, Italy, for their assistance in the characterisation
of the compounds described herein.
References and notes
1. Tatemoto, K.; Carlquist, M.; Mutt, V. Nature 1982, 296,
659.
2. O’Donohue, T. L.; Chronwall, B. M.; Pruss, R. M.;
Mezey, E.; Kiss, J. Z.; Eiden, L. E.; Massari, J.; Tessel, E.;