5642
M. Belley et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5639–5642
C.; Denis, D.; Metters, K. M. Bioorg. Med. Chem. 2001, 9,
1977; (b) Juteau, H.; Gareau, Y.; Labelle, M.; Lamonta-
Several splice variants of the EP3 receptor, defined by
different C-terminal cytoplasmic tails, have been discov-
ered.10 Their localization in the body and their physio-
logic significance remain uncertain. The antagonists
described here may bind in a different manner to these
splice variants and it is also possible that only binding
to a specific splice variant may be effective for the reduc-
tion of fever and/or hyperalgesia.
`
gne, S.; Tremblay, N.; Carriere, M.-C.; Denis, D.; Sawyer,
N.; Metters, K. M. Bioorg. Med. Chem. Lett. 2001, 11,
747.
3. Most of the compounds reported in Table 1 are mixtures
of two isomers, but we have shown previously that the
difference of activity between these isomers is 2-fold on the
EP3 receptor,1 and the variation in the ratio of isomers
should not significantly change the results described
herein.
4. Pelletier, J. C.; Hesson, D. P. Synlett 1995, 1141.
5. Boie, Y.; Stocco, R.; Sawyer, N.; Slipetz, D. M.;
Ungrin, M. D.; Neuscha¨fer-Rube, F.; Puschel, G. P.;
¨
Metters, K. M.; Abramovitz, M. Eur. J. Pharmacol.
1997, 340, 227.
6. Li, C.; Chauret, N.; Trimble, L. A.; Nicoll-Griffith, D. A.;
Silva, J. M.; Macdonald, D.; Perrier, H.; Yergey, J. A.;
Parton, T.; Alexander, R. P.; Warrellow, G. J. Drug
Metab. Dispos. 2001, 29, 232.
In summary, we have compared here the activity and
biological profile in vivo of two different series of very
potent and selective EP3 antagonists: the ortho-substi-
tuted cinnamic acids 1–3 and the acylsulfonamides of
ortho-(arylmethyl)cinnamates 7. Compounds 1a/2a, 1e,
and 7b–c all showed good anti-inflammatory properties,
as measured by the rat paw edema assay. Curiously, the
analgesic activity of 1a/2a, 1e, and 7a–f varies a lot from
one compound to the next and seems not to be propor-
tional to their potency on the EP3 receptor, nor to their
plasma concentration. Further studies will be needed to
really understand why very potent and selective EP3
antagonists are not always efficacious in the rat paw
hyperalgesia model.
7. Chan, C.-C.; Boyce, S.; Brideau, C.; Ford-Hutchinson, A.
W.; Gordon, R.; Guay, D.; Hill, R. G.; Li, C.-S.; Mancini,
J.; Penneton, M.; Prasit, P.; Rasori, R.; Riendeau, D.;
Roy, P.; Tagari, P.; Vickers, P.; Wong, E.; Rodger, I. W.
J. Pharm. Exp. Ther. 1995, 274, 1531.
8. (a) Labelle, M.; Gareau, Y.; Dufresne, C.; Lau, C. K.;
Belley, M.; Jones, T. R.; Leblanc, Y.; McAuliffe, M.;
McFarlane, C. S.; Metters, K. M.; Ouimet, N.;
Perrier, H.; Rochette, C.; Sawyer, N.; Slipetz, D.;
Xiang, Y. B.; Wang, Z.; Pickett, C. B.; Ford-Hutch-
inson, A. W.; Young, R. N.; Zamboni, R. J. Bioorg.
Med. Chem. Lett. 1995, 5, 2551; (b) Jones, T. R.;
Labelle, M.; Belley, M.; Champion, E.; Charette, L.;
Evans, J.; Ford-Hutchinson, A. W.; Gauthier, J.-Y.;
Lord, A.; Masson, P.; McAuliffe, M.; McFarlane, C.
S.; Metters, K. M.; Pickett, C.; Piechuta, H.; Rochette,
C.; Rodger, I. W.; Sawyer, N.; Young, R. N.;
Zamboni, R. J.; Abraham, W. M. Can. J. Physiol.
Pharmacol. 1995, 73, 191.
Acknowledgments
The authors thank Renee Aspiotis for proofreading this
manuscript and Jose Silva for the preparation of rat and
human hepatocytes.
References and notes
1. Belley, M.; Gallant, M.; Roy, B.; Houde, K.; Lachance,
N.; Labelle, M.; Trimble, L.; Chauret, N.; Li, C.; Sawyer,
9. The Ki for the IP, TP, FP, and DP receptors for the
compounds included in Table 3 are all above 0.5 lM, with
the exception of 7d which shows a Ki of 0.082 lM on the
DP receptor.
`
N.; Tremblay, N.; Lamontagne, S.; Carriere, M.-C.;
Denis, D.; Greig, G. M.; Slipetz, D.; Metters, K. M.;
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M. D. Annu. Rev. Pharmacol. Toxicol. 2001, 41, 661.
2. (a) Juteau, H.; Gareau, Y.; Labelle, M.; Sturino, C. F.;
`
Sawyer, N.; Tremblay, N.; Lamontagne, S.; Carriere, M.-