1446
C. W. Plummer et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1441–1446
Calandra, B.; Pecceu, F.; Lupker, J.; Maffrand, J. P.; Le
Fur, G.; Casellas, P. J. Biol. Chem. 1997, 272, 22330.
11. Shim, J.-Y.; Welsh, W. J.; Cartier, E.; Edwards, J. L.;
Howlett, A. C. J. Med. Chem. 2002, 45, 1447.
12. Lange, J. H. M.; van Stuivenberg, H. H.; Coolen, H. K. A.
C.; Adolfs, T. J. P.; McCreary, A. C.; Keizer, H. G.; Wals,
H. C.; Veerman, W.; Borst, A. J. M.; de Looff, W.;
Verveer, P. C.; Kruse, C. G. J. Med. Chem. 2004; web
release.
13. (a) Finke, P. E.; Meurer, L. C.; Debenham, J. S.;
Toupence, R. B.; Walsh, T. F. WO Patent 03/082191
A2, 2003; Chem. Abstr. 2003, 139, 307686f; (b) Meurer, L.
C.; Finke, P. E.; Mills, S. G.; Walsh, T. F.; Toupence, R.
B.; Debenham, J. S.; Goulet, M. T.; Wang, J.; Tong, X.;
Fong, T. M.; Lao, J.; Schaeffer, M.-T.; Chen, J.; Shen,
C.-P.; Stribling, D. S.; Shearman, L. P.; Strack, A. M.;
Van der Ploeg, L. H. T. Bioorg. Med. Chem. Lett. 2005,
15, 645.
14. Barth, F.; Martinez, S.; Rinaldi-Carmona, M. WO Patent
03/084930 A1, 2003; Chem. Abstr. 2003, 139, 307689j.
15. 1H NMR and/or MS data for all new compounds were in
agreement with the assigned structures. For full experi-
mental and representative NMR spectral data, see: Finke,
P. E.; Mills, S. G.; Plummer, C. W.; Shah, S. K.; Truong,
T. Q. WO Patent 03/007887-A2, 2003; Chem. Abstr. 2003,
138, 122647e.
orally bioavailable with good pharmacokinetics. These
compounds were also shown to be efficacious in obese
rat feeding studies, showing reductions in both food in-
take and overall body weight. In addition, the N-ethyl
derivative 25b was shown to be equally potent. These
findings might allow some flexibility in the selection of
derivatives in the future with enhanced PK and CNS
exposure profiles with improved physical and/or off-
target properties. Further SAR studies of both the C-2
amide and N-1 alkyl group will be published elsewhere
in the near future.
Acknowledgements
The authors are grateful to Quang Truong for the prep-
aration of additional 24b for the feeding study.
Supplementary data
Supplementary data associated with this article can be
16. A small amount of unsubstituted N–H imidazole (<10%)
was usually formed as a by-product from disproportion-
ation of the N-methyl urea to urea during the reaction and
was removed in subsequent purifications.
References and notes
17. Kim, Y. B.; Kim, C. S.; Lee, C. K. J. Heterocyclic Chem.
1994, 31, 1653.
18. Bredereck, H.; Gompper, R.; Rempfer, H.; Klemm, K.;
Keck, H. Chem. Ber. 1959, 92, 329.
19. See the supplementary data for the NOE NMR spectral
data for the structural assignment of 24b and 26b and the
HMBC NMR experiment for the assignment of 28b and
29b.
20. The reported binding results ( SD) were an average of 2–8
independent determinations (each done in replicate) which
were normally within 50% of the average value based on a
standard sample. For both the binding and functional
assay conditions, see Ref. 21.
1. (a) Flegal, K. M.; Carroll, M. D.; Ogden, C. L.; Johnson,
C. L. J. Am. Med. Assoc. 2002, 288, 1723; (b) Yanovski, S.
Z.; Yanovski, J. A. New Engl. J. Med. 2002, 346, 591.
2. For general reviews of cannabinoid receptor ligands and
potential therapeutic applications, see: (a) Di Carlo, G.;
Izzo, A. A. Exp. Opin. Invest. Drugs 2003, 12, 39; (b)
Pertwee, R. G. Exp. Opin. Invest. Drugs 2000, 9, 1553; (c)
Xiang, J.-N.; Lee, J. C. Annu. Rep. Med. Chem. 1999, 34,
199.
3. Trillou, R. C.; Arnone, C.; Gonalons, N.; Keane, P.;
Maffrand, J. P.; Soubrie, P. J. Physiol. Regul. Integr.
Comp. Physiol. 2003, 284, 345.
4. Rinaldi-Carmona, M.; Barth, F.; Heaulme, M.; Shire, D.;
Calandra, B.; Congy, C.; Martinez, S.; Maruani, J.;
Neliat, G.; Caput, D.; Ferrarra, P.; Soubrie, P.; Breliere,
J. C.; Le Fur, G. FEBS Lett. 1994, 350, 240.
5. Barth, F.; Rinaldi-Carmona, M. Curr. Med. Chem. 1999,
6, 745.
21. Felder, C. C.; Joyce, K. E.; Briley, E. M.; Mansouri, J.;
Mackie, K.; Blond, O.; Lai, Y.; Ma, A. L.; Mitchell, R. L.
Mol. Pharmacol. 1995, 48, 443.
22. See the supplementary data for a complete listing of CB2
binding data.
23. Male Sprague–Dawley rats were dosed at 1.0 mg/kg iv via
an implanted cannula (n = 1 (24b) or 2 (24a)) and at
2.0 mg/kg po by gavage (n = 3). Compounds were formu-
lated at 1 mg/mL in TWEEN 80:EtOH:water (10:23:67)
for both the iv and po doses. Plasma concentrations were
6. Colombo, G.; Agabio, R.; Diaz, G.; Lobina, C.; Reali, R.;
Gessa, G. L. Life Sci. 1998, 8, 113.
7. Pertwee, R. G. Pharmacol. Ther. 1997, 74, 129.
8. Koe, B. K.; Milne, G. M.; Weissman, A.; Johnson, M. R.;
Melvin, L. S. Eur. J. Pharmacol. 1985, 109, 201.
9. Mato, S.; Pazos, A.; Valdizan, E. M. Eur. J. Pharmacol.
2002, 443, 43.
10. (a) Landsman, R. S.; Burkey, T. H.; Consroe, P.; Roeske,
W. R.; Yamamura, H. I. Eur. J. Pharmacol. 1997, 334R1–
334R2; (b) Bouaboula, M.; Perrachon, S.; Milligan, L.;
Canat, X.; Rinaldi-Carmona, M.; Portier, M.; Barth, F.;
determined
precipitation.
by
LC–MS/MS
following
protein
24. Male Sprague-Dawley rats were dosed at 1.0 mg/kg iv
(n = 3 at each time point) via the tail vein. Compounds
were formulated at 1 mg/mL in TWEEN 80:EtOH:water
(10:23:67). Plasma and brain concentrations were deter-
mined by LC–MS/MS.