2690
A. Hall et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2684–2690
3. (a) McKeown, S. C.; Hall, A.; Blunt, R.; Brown, S. H.;
Chessell, I. P.; Chowdhury, A.; Giblin, G. M. P.; Healy,
M. P.; Johnson, M. R.; Lorthioir, O.; Michel, A. D.;
Naylor, A.; Lewell, X.; Roman, S.; Watson, S. P.;
Winchester, W. J.; Wilson, R. J. Bioorg. Med. Chem.
Lett. 2007, 17, 1750; (b) Hall, A.; Brown, S. H.; Chessell, I.
P.; Chowdhury, A.; Giblin, G. M. P.; Gibson, M.; Healy,
M. P.; Livermore, D. G.; McArthur Wilson, R. J.; Naylor,
A.; Rawlings, D. A.; Roman, S.; Ward, E.; Willay, C.
Bioorg. Med. Chem. Lett. 2007, 17, 4450.
4. McKeown, S. C.; Hall, A.; Giblin, G. M. P.; Lorthioir, O.;
Blunt, R.; Lewell, X. Q.; Wilson, R. J.; Brown, S. H.;
Chowdhury, A.; Coleman, T.; Watson, S. P.; Chessell, I.
P.; Pipe, A.; Clayton, N. M.; Goldsmith, P. Bioorg. Med.
Chem. Lett. 2006, 16, 4767.
(EP1 FLIPR pKi 10.2, EP3 FLIPR pKi 6.3), 12c (EP1
FLIPR pKi 8.9, EP3 FLIPR pKi 6.3, TP FLIPR pKi
6.4), 12g (EP1 FLIPR pKi 7.7, EP3 FLIPR pKi 6.1).
In conclusion, we have identified a novel series of indole
EP1 receptor antagonists by scaffold hopping and ex-
plored the SAR in the 1-, 2-, 3-, 5-, and 6-positions.
Although there are similarities between the SAR in this
series and previous series there is some divergence, in
particular the 3-position which forms a lipophilic inter-
action. Several compounds with high in vitro affinity
were identified. From this, compound 12g was found
to combine the best balance of in vitro DMPK proper-
ties and in vitro EP1 activity and was thus assessed in an
in vivo model of inflammatory pain where it showed
excellent efficacy, with an ED50 of 2.17 mg/kg, and
equivalent efficacy to celecoxib.
5. Hall, A.; Billinton, A.; Giblin, G. M. P. Curr. Opin. Drug
Disc. Development 2007, 10, 597.
6. Hall, A.; Bit, R. A.; Brown, S. H.; Chowdhury, A.;
Giblin, G. M. P.; Hurst, D. N.; Kilford, I. R.; Lewell,
X.; Naylor, A.; Scoccitti, T. Bioorg. Med. Chem. Lett.
2008, 18, 1592.
7. Molecular minimization and overlays conducted using
MOE (Molecular Operating Environment), Chemical
8. Compound potencies were determined using a radioligand
binding assay where the ability of compounds to compete
with tritiated prostaglandin E2 ([3H]-PGE2) binding to the
human EP1 receptor was measured in Chinese hamster
ovary-K1 (CHO-K1) cells into which a stable vector
containing the EP1 cDNA had previously been transfec-
ted. Cell membranes, competing compounds and [3]-PGE2
(3 nM final assay concentration) were incubated in a final
volume of 100 ll for 30 min at 30 °C. The radioactivity
retained was measured by liquid scintillation counting in
Packard TopCount scintillation counter.
9. The antagonist properties of compounds were assessed by
their ability to inhibit the mobilization of intracellular
calcium ([Ca2+]i) in response to activation of the EP1
receptor by prostaglandin E2 (PGE2). The amount of
calcium produced was assessed using a calcium-sensitive
fluorescent dye such as Fluo-3, AM and a suitable
instrument such as a Fluorimetric Imaging Plate Reader
(FLIPR).
10. Clarke, S. E.; Jeffrey, P. Xenobiotica 2001, 31 (8/9), 591.
11. Giblin, G. M. P.; Hall, A.; Hurst, D. N.; Scoccitti, T.;
Theobald, P. J. WO2008006790A1, 2008.
12. Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 11684.
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Acknowledgments
We thank Emma Ward for generating data in the
FLIPR assay and Anabel Molero Milan for the first syn-
thesis of compound 10a.
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