3314
H. Omura et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3310–3314
Table 4. The pharmacological profile of compound 39
Zvonok, A.; Cockayne, D. A.; Kwan, J.; Mata, H. P.;
Vanderah, T. W.; Lai, J.; Porreca, F.; Makriyannis, A.;
Malan, T. P., Jr. Proc. Natl. Acad. Sci. U.S.A. 2003, 100,
10529; (c) Makriyannis, A.; Deng, H. WO02/060447.
6. Hanus, L.; Breuer, A.; Tchilibon, S.; Shiloah, S.; Golden-
berg, D.; Horowitz, M.; Pertwee, R. G.; Ross, R. A.;
Mechoulam, R.; Fride, E. Proc. Natl. Acad. Sci. U.S.A.
1999, 96, 14228.
hCB2 Ki
8 nM
2 nM
118%
1459 nM
182
hCB2 EC50
hCB2 Emax
hCB1 Ki
Selectivity CB1/CB2
HLM T1/2
>120 min
33%
2.2
Bioavailability in rat
logDa
7. Malan, T. P., Jr.; Ibrahim, M. M.; Lai, J.; Vanderah, T.
W.; Makriyannis, A.; Porreca, F. Curr. Opin. Pharmacol.
2003, 3, 62.
a At pH 7.4.
8. Cannabinoids for pain therapeutics, see (a) Di Marzo, V.;
Bifulco, M.; De Petrocellis, L. Nat. Rev. Drug Discov.
2004, 3, 771; (b) Huang, S. M.; Walker, J. M. Cannabi-
noids Ther. 2005, 149; (c) Ben Amar, M. J. Ethnophar-
macol. 2006, 105, 1; (d) Whiteside, G. T.; Lee, G. P.;
Valenzano, K. J. Curr. Med. Chem. 2007, 14, 917.
9. Compound 1: D’Ambra, T. E.; Estep, K. G.; Bell, M. R.;
Eissenstat, M. A.; Josef, K. A.; Ward, S. J.; Haycock, D.
A.; Baizman, E. R.; Casiano, F. M.; Beglin, N. C.;
Chippari, S. M.; Grego, J. D.; Kullnig, R. K.; Daley, G. T.
J. Med. Chem. 1992, 35, 124.
of metabolic stability by structural changes around met-
abolic sites and/or the reduction of molecular lipophilic-
ity. The SAR study starting from 9 resulted in the
discovery of 39 as the best compound. 39 showed 180-
fold CB2 selectivity over CB1, excellent metabolic stabil-
ity in HLM, and oral activity in rat visceral allodynia.
10. Compound 3: (a) Hynes, J., Jr.; Leftheris, K.; Wu, H.;
Pandit, C.; Chen, P.; Norris, D. J.; Chen, B.-C.; Zhao, R.;
Kiener, P. A.; Chen, X.; Turk, L. A.; Patil-Koota, V.;
Gillooly, K. M.; Shuster, D. J.; McIntyre, K. W. Bioorg.
Med. Chem. Lett. 2002, 12, 2399; (b) Wrobleski, S. T.;
Chen, P.; Hynes, J., Jr.; Lin, S.; Norris, D. J.; Pandit, C.
R.; Spergel, S.; Wu, H.; Tokarski, J. S.; Chen, X.;
Gillooly, K. M.; Kiener, P. A.; McIntyre, K. W.; Patil-
koota, V.; Shuster, D. J.; Turk, L. A.; Yang, G.; Leftheris,
K. J. Med. Chem. 2003, 46, 2110.
Acknowledgments
We thank Mr. Masatoshi Masuda and Dr. Hiroyuki
Nishida for metabolites identification studies, and Ms.
Misaki Suzuki for ADME screening data. We are also
grateful to Ms. Katsuyo Ohashi for in vivo assay and
Dr. Hiroki Sone for useful discussions on this study.
11. Compound 4: Makriyannis, A.; Liu, Q. WO03/035005.
12. Toxicity of aniline was reported. see: (a) Famulok, M.;
Boche, G. Angew. Chem., Int. Ed. Engl. 1989, 28, 468; (b)
Marques, M. M.; Mourato, L. L. G.; Amorim, M. T.;
Santos, M. A.; Melchior, W. B., Jr.; Beland, F. A. Chem.
Res. Toxicol. 1997, 10, 1266.
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Refs. 2e,10b.
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benzimidazolone ring of compound 34 enhanced its CB2
binding activity up to 5 nM from 338 nM. Similar study of
substituent effect was reported. see: Ref. 10a.
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18. See Ref. 13 for the assay protocol.