1452
J. S. Debenham et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1448–1452
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418.
showed greatly reduced GABAA activity (about 22% inhibition at
10 M) and were devoid of adverse neurological effects after dos-
ing CD1 mice at 500 mg/kg.
l
7. Cota, D.; Marsicano, G.; Tschöp, M.; Grübler, Y.; Flachskamm, C.; Schubert, M.;
Auer, D.; Yassouridis, A.; Thöne-Reinecke, C.; Ortmann, S.; Tomassoni, F.;
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Debenham, J. S.; 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.; MacIntyre, D. E.; Van
der Ploeg, L. H. T.; Goulet, M. T. Bioorg. Med. Chem. Lett. 2005, 15, 645; (b)
Madsen-Duggan, C.; Debenham, J. S.; Walsh, T. F.; Toupence, R. B.; Huang, S. X.;
Wang, J.; Tong, X.; Lao, J.; Fong, T. M.; Schaeffer, M.-T.; Xiao, J. C.; Shen, C.-P.;
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Lao, J.; Yu, H.; Feng, Y.; Xiao, J. C.; Van der Ploeg, L. H. T.; Goulet, M. T.;
Hagmann, W. K.; Lin, L. S.; Lanza, T. J., Jr.; Jewell, J. P.; Liu, P.; Shah, S. K.; Qi, H.;
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In summary, we have shown that the heterobicyclic furo[2,3-
b]pyridines exemplified by 7g and 7f are potent CB1R inverse ago-
nists that are effective in modulating feeding behavior to suppress
both FI and BW gain. These effects were determined to be
mechanism based. While the efficacy, physical properties, pharma-
cokinetics, drug metabolism and disposition were acceptable,
off-target GABAA activity in lead compound 7g prevented clinical
advancement. Further SAR studies to avoid GABAA activity, phar-
macological evaluation and safety profiling of alternative furopyri-
dine analogs will be reported in due course.
Acknowledgments
10. Debenham, J. S.; Madsen-Duggan, C. B.; Walsh, T. F.; Wang, J.; Tong, X.; Doss, G.
A.; Lao, J.; Fong, T. M.; Schaeffer, M.-T.; Xiao, J. C.; Huang, C. R.-R. C.; Shen, C.-P.;
Feng, Y.; Marsh, D. J.; Stribling, D. S.; Shearman, L. P.; Strack, A. M.; MacIntyre,
D. E.; Van der Ploeg, L. H. T.; Goulet, M. T. Bioorg. Med. Chem. Lett. 2006, 16, 681.
11. Debenham, J. S.; Madsen-Duggan, C. B.; Wang, J.; Tong, X.; Lao, J.; Fong, T. M.;
Schaeffer, M.-T.; Xiao, J. C.; Huang, C. R.-R. C.; Shen, C.-P.; Stribling, D. S.;
Shearman, L. P.; Strack, A. M.; MacIntyre, D. E.; Hale, J. J.; Walsh, T. F. Bioorg.
Med. Chem. Lett. 2009, 19, 2591.
12. The reported binding results were an average of 2–8 independent
determinations (each done in replicate) which were normally within 50% of
the average value. For both the binding and functional assay conditions, see:
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.
We thank Keith Wafford, Marie-Therese Schaeffer, Hugo M.
Vargas, Patricia B. Bunting, Erin McGowan, Doreen Cashen, Bill
Martin and William K. Hagmann for their contributions toward this
study.
References and notes
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respectively Flum, D. R.; Salem, L.; Dellinger, E. P.; Cheadle, A.; Chan, L. J. Am.
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13. Feces were not collected.
14. HPLC Log D values were determined at pH 7.3.
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Fernandes, C.; Goya, P. Curr. Top. Med. Chem. 2008, 8, 205; For other
heterobicyclic CB1 modulators see: (b) Griffith, D. A.; Hadcock, J. R.; Black, S.
C.; Iredale, P. A.; Caprino, P. A.; Dasilva-Jardine, P.; Day, R.; DiBrino, J.; Dow, R.
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Addy, C.; Li, S.; Agrawal, N.; Stone, J.; Majumdar, A.; Zhong, L.; Li, H.; Yuan, J.;
15. C57BL/6 mice were purchased from Taconic Farms. Cnr1 knockout mice were
generated by the laboratory of Dr. Andreas Zimmer, National Institute of
Mental Health, NIH (Zimmer, A.; Zimmer, A. M.; Hohmann, A. G.; Herkenham,
M.; Bonner, T. I. Proc. Natl. Acad. Sci. 1999, 96, 5780) and generously provided
by him.
16. Experimental methods were similar to that described in Ref. 10 except 7g was
only dosed at 1 and 3 mg/kg based on its improved efficacy.
17. Rats were monitored for 120 h.
18. Discovery Pharmacology services provided by MDS Pharma Services, Taipei,
Taiwan.
19. A rotarod test is used to assess the rodent’s sensomotor coordination by
evaluating how long it can remain on a rotating rod with a steady or increasing
rate of rotation.