B. Dyck et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1151–1154
1153
Based on these studies, it is clear that high affinity bind-
ing of compounds such as SR141716 to the CB1 recep-
tor relies more heavily on the nature of the side chains,
rather than the heterocycle itself. A small substituent
such as methyl or cyano on the azole core appears to be
important for high affinity binding, possibly by orient-
ing the amide nitrogen substituent. The absence of this
small group has a detrimental effect on binding affinity
that cannot easily be overcome by substituting the
adjacent phenyl group. In the triazole series, it appears
possible to incorporate hydrophilic groups into the
amide substituent. Although this may be pertinent to
the pursuit of less lipophilic analogues which have a
variety of applications,20 the fact that this introduction
inevitably requires an additional lipophile to compen-
sate cannot be underestimated. The cannabinoid recep-
tors endogenous ligands are very liphophilic in nature
and it appears that from this study a high affinity
antagonist will necessarily be very lipophilic as well.
Scheme 3. Reagents: (a) (i) 4-ClC6H4NH2, AlCl3, 150 ꢀC; (ii) ethyl
bromopyruvate, K2CO3, EtOH, reflux (24%); (iii) Br2, ACN (88%);
(b) (i) aq NaOH, dioxane, 70 ꢀC (100%); (ii) oxalyl chloride, DCM,
cat. DMF; (iii) R1R2NH, ACN; (iv) Bu3SnR3 or SnMe4, trifurylphos-
phine, Pd2dba3, NMP, 60 ꢀC (13–60%).
converted to diarylimidazolecarboxylate 29a by reaction
with ethyl bromopyruvate under acidic conditions.24,25
Imidazole 29a was then converted to the corresponding
imidazolecarboxamides 31–35 as described above for
the pyrazole- and triazole-based carboxamides. For-
tunately, the imidazole core allowed for the introduc-
tion of an additional substituent such as the methyl
group present in SR141716 (4), an opportunity una-
vailable in the triazole series. For this reason, a portion
of 29a was brominated to give 29b, which in turn was
converted to the analogous amides. With the bromi-
nated amides 30 (R3=Br) in hand, coupling with orga-
nostannanes under Stille-like conditions26 enabled the
introduction of a variety of substituents at this position.
References and notes
1. Razdan, R. K.; Howes, J. F. Med. Res. Rev. 1983, 3, 119.
2. Hollister, L. E. Pharmacol. Rev. 1986, 38, 1.
3. Pertwee, R. G. Pharmacol. Ther. 1988, 36, 189.
4. Abood, M. E.; Martin, B. R. Trends Pharmacol. Sci.
1992, 13, 201.
5. Howlett, A. C. Annu. Rev. Pharmacol. Toxicol 1995, 35,
607.
6. Pertwee, R. G. Pharmacol. Ther. 1997, 74, 129.
7. Felder, C. C.; Glass, M. Annu. Rev. Pharmacol. Toxicol.
1998, 38, 179.
8. Piomelli, D.; Giuffrida, A.; Calignano, A.; de Fonseca,
F. R. Trends Pharmacol. Sci. 2000, 21, 218.
9. Devane, W. A.; Hanus, L.; Breuer, A.; Pertwee, R. G.;
Stevenson, L. A.; Griffin, G.; Gibson, D.; Mandelbaum,
A.; Etinger, A.; Mechoulam, R. Science 1992, 258, 1946.
10. Smith, P. B.; Compton, D. R.; Welch, S. P.; Razdan,
R. K.; Mechoulam, R.; Martin, B. R. J. Pharmacol. Exp.
Ther. 1994, 270, 219.
11. Jarbe, T. U. C.; Sheppard, R.; Lamb, R. J.; Makriyannis,
A.; Lin, S.; Goutopoulos, A. Behav. Pharmacol. 1998, 9,
169.
12. Barth, F.; Rinaldi-Carmona, M. Curr. Med. Chem. 1999,
6, 745.
13. SR141716 has been reported to behave as an inverse ago-
nist under some experimental settings: Bouaboula, M.;
Perrachon, S.; Milligan, L.; Canat, X.; Rinaldi-Carmona,
M.; Portier, M.; Barth, F.; Calandra, B.; Pecceu, F.;
Lupker, J.; Maffrand, J.-P.; Le Fur, G.; Casellas, P. J.
Biol. Chem. 1997, 272, 22330.
The activities of the imidazole compounds in the CB1
receptor binding assay are presented in Table 3. The
simple examples 31–34 were approximately 2-fold more
potent than their triazole counterparts, but up to 10-
fold less potent than the related pyrazoles. When sub-
stituted with groups other than hydrogen, the imida-
zoles showed potencies comparable to their pyrazole
counterparts. With the bicyclic hydrazide substituent,
the bromo- (36), cyano- (37) and methylimidazoles (38)
possess Ki’s ranging from 9 to 14 nM. Other analogues
in the methyl-substituted imidazole series such as 40
showed a comparable increase in potency relative to the
triazole analogues. Interestingly, an acetylenic sub-
stituent at this position drastically dropped the potency
(39). The inhibition constant of imidazole 38 is twice
that of the related pyrazole 5, and is virtually equipotent
to the clinical candidate SR141716 (4). Compound 38
exhibited an IC50 of 19Æ2 nM (n=2) in a GTPgS assay,
demonstrating that it is a functional antagonist.
Table 3. Binding affinities of imidazoles 30 for the CB1 receptor
14. Barth, F.; Casellas, P.; Congy, C.; Martinez, S.; Rinaldi,
M.; Anne-Archard, G. US Patent 5,624,941, 1997.
15. Rinaldi-Carmona, M.; Barth, F.; Heaulme, M.; Shire, D.;
Calandra, B.; Congy, C.; Martinez, S.; Maruani, J.;
Neliat, G.; Caput, D.; Ferrara, P.; Soubrie, P.; Breliere,
J. C.; Le Fur, G. FEBS Lett. 1994, 350, 240.
16. Thomas, B. F.; Gilliam, A. F.; Burch, D. F.; Roche, M. J.;
Seltzman, H. H. J. Pharmacol. Exp. Ther. 1998, 285,
285.
17. Lan, R.; Liu, Q.; Fan, P.; Lin, S.; Fernando, S. R.;
McCallion, D.; Pertwee, R.; Makriyannis, A. J. Med.
Chem. 1999, 42, 769.
18. Howlett, A. C.; Wilken, G. H.; Pigg, J. J.; Houston, D. B.;
Lan, R.; Liu, Q.; Makriyannis, A. J. Neurochem. 2000, 74,
2174.
Compd
R1
R2
R3
KiÆSEM
(nM)a
31
32
33
34
35
36
37
38
39
40
H
H
H
H
H
H
H
H
H
H
1-Piperidinyl
H
H
H
H
H
Br
CN
Me
CCH
Me
85Æ16
66Æ11
78Æ14
48Æ19
(48)b
3-Azabicyclo[3.3.0]octan-3-yl
1-Homopiperidinyl
Cyclohexyl
2-(Dimethylamino)ethyl
3-Azabicyclo[3.3.0]octan-3-yl
3-Azabicyclo[3.3.0]octan-3-yl
3-Azabicyclo[3.3.0]octan-3-yl
3-Azabicyclo[3.3.0]octan-3-yl
1-(4-Chlorophenyl)ethyl
11Æ4
9Æ1
14Æ4
770Æ206
33Æ9
a Values are averaged from at least three experiments.
b Inhibition (%) at 20 mM.