920
A. Hall et al. / Bioorg. Med. Chem. Lett. 17 (2007) 916–920
CO2Me
OCHF2
H2N
H2N
CO2Me
OMe
O2N
CO2Me
OH
a, b
c, b
6
5
7
Scheme 1. Reagents and conditions: (a) ClCF2CO2Na, Na2CO3, DMF, 100 °C; (b) H2, Pd/C, EtOH; (c) NaH, MeI, DMF.
O
O
O
H2N
H2N
O2N
b, a
a
OMe
OMe
OMe
N
H
NH2
NO2
9
8
10
Scheme 2. Reagents and conditions: (a) H2, Pd/C, MeOH; (b) DMF–DMA, DMF, 60 °C, lwave, 15 min.
Toxicol. 2001, 41, 661; (c) Narumiya, S.; Sugimoto, Y.;
Ushikubi, F. Physiol. Rev. 1999, 79, 1193; (d) Coleman, R.
A., Kennedy, I., Humphrey, P. P. A., Bunce, K., Lumley,
P., Eds.; Comprehensive Medicinal Chemistry; 1990, Vol. 3,
Pergamon: Oxford, UK, p 643.
be prepared by reduction of the analogous nitro
derivative.
Methyl 5-amino-2-(methyloxy)benzoate 6 and methyl 5-
amino-2-[(difluoromethyl)oxy]benzoate 7 were prepared
from 5 as detailed in Scheme 1. Paal-Knorr condensa-
tion7 with the appropriate 1,4-diketone followed by ester
hydrolysis yielded derivatives 1m–o. The condensation
reaction was conducted under thermal (PhMe, pTSA,
reflux) or microwave (NMP, pTSA, 150 °C, 10 min)
conditions.
2. Huntjens, D. R. H.; Danhof, M.; Della Pasqua, O. E.
Rheumatology 2005, 44, 846.
3. Stock, L. S.; Shinjo, K.; Burkhardt, J.; Roach, M.;
Taniguchi, K.; Ishikawa, T.; Kim, H.-S.; Flannery, P. J.;
Coffman, T. M.; McNeish, J. D.; Audoly, L. P. J. Clin.
Invest. 2001, 107, 325.
4. (a) Omote, K.; Kawamata, T.; Nakayama, Y.; Kawa-
mata, M.; Hazama, K.; Namiki, A. Anesth. Analg. 2001,
92, 233; (b) Omote, K.; Yamamoto, H.; Kawamata, T.;
Nakayama, Y.; Namiki, A. Anesth. Analg. 2002, 95,
1708.
5. Kawahara, H.; Sakamoto, T.; Takeda, S.; Onodera, H.;
Imaki, J.; Ogawa, R. Anesth. Analg. 2001, 93, 1012.
6. Maruyama, T.; Koketsu, M.; Yaamamoto, H.; Yamam-
oto, K.; Yamamoto, L. T.; Hayashida, K.-i.; Ohchida, S.;
Kondo, K. Prostaglandins and Other Lipid Mediators
1999, 59, 217.
Methyl 3,5-diamino-2-methylbenzoate 9 was prepared
from 8 as detailed in Scheme 2. Paal-Knorr condensation
took place selectively with the less hindered 5-amino
moiety, to give derivatives 2a–f, upon basic hydrolysis
of the ester group. Methyl 6-amino-1H-indole-4-carbox-
ylate 10 was prepared as described in Scheme 2 and used
without purification to prepare compound 4.
7. Hall, A.; Atkinson, S.; Brown, S. H.; Chessell, I. P.;
Chowdhury, A.; Clayton, N. M.; Coleman, T.; Giblin, G.
M. P.; Gleave, R. J.; Hammond, B.; Healy, M. P.;
Johnson, M. J.; Michel, A. D.; Naylor, A.; Novelli, R.;
Spalding, D. J.; Tang, S. P. Bioorg. Med. Chem. Lett.
2006, 16, 3657.
8. Hall, A.; Bit, R. A.; Brown, S. H.; Chaignot, H. M.;
Chessell, I. P.; Coleman, T.; Giblin, G. M. P.; Hurst, D.
N.; Kilford, I. R.; Lewell, X. Q.; Michel, A. D.; Moham-
ed, S.; Naylor, A.; Novelli, R.; Skinner, L.; Spalding, D.
J.; Tang, S. P.; Wilson, R. J. Bioorg. Med. Chem. Lett.
2006, 16, 2666, and references therein.
In conclusion, substitution of the benzoic acid moiety of
the 1,5-biaryl pyrrole template led to the identification
of compounds with sub-nanomolar affinity for the EP1
receptor. Several analogues showed good oral exposure
and efficacy in a preclinical model of inflammatory pain.
Compound 1h (GW855454X) demonstrated good meta-
bolic stability, good bioavailability and excellent efficacy
in established FCA model of inflammatory pain with an
ED50 of 2.5–4.9 mg/kg. These data support the use of 1h
as a tool compound to elucidate the in vivo effects of
EP1 receptor antagonism.
9. Hall, A.; Brown, S. H.; Chessell, I. P.; Chowdhury, A.;
Clayton, N. M.; Coleman, T.; Giblin, G. M. P.; Ham-
mond, D.; Healy, M. P.; Johnson, M. R.; Metcalf, A.;
Michel, A. D.; Naylor, A.; Novelli, R.; Spalding, D. J.;
Sweeting, J. Bioorg. Med. Chem. Lett. 2006, 16.
10. (a) Giblin, G. M. P.; Hall, A.; Healy, M. P.; Lewell, X. Q.;
Miller, N. D.; Novelli, R. WO2003/101959A1.; (b) Giblin,
G. M. P.; Hall, A.; Healy, M. P.; Lewell, X. Q.; Miller, N.
D.; Novelli, R.; King, F. D.; Naylor, A. WO2005/
054191A1.
Acknowledgments
The authors thank Emma Ward for generating the EP1
and EP3 FLIPR data and Davina Mitchell for generat-
ing the FP data.
References and notes
11. ED50 = 2.5 mg/kg when dose–response assay carried out
at doses of 1, 3 and 10 mg/kg, ED50 = 4.9 mg/kg when
dose–response assay carried out at 3, 10 and 30 mg/kg.
1. (a) Coleman, R. A.; Smith, W. L.; Narumiya, S. Pharma-
col. Rev. 1994, 46, 205; (b) Breyer, R. M.; Bagdassarian, C.
K.; Myers, S. A.; Breyer, M. D. Annu. Rev. Pharmacol.