4536
S. M. Westaway et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4533–4536
Table 5. Antagonist activity (FLIPR) of 46 versus capsaicin and acid
at human, rat and guinea pig TRPV1 receptors
Lee, J.; Suh, Y.; Cho, H.; Oh, U.; Kim, H.; Joo, Yung H.;
Kim, S.; Park, Y.; Jeong, Y.; Choi, J. K.; Kim, J. K.; Jew,
S. Bioorg. Med. Chem. Lett. 2004, 14, 1693.
O
8. (a) Park, H.; Choi, J.; Kim, M.; Choi, S.; Park, M.; Lee, J.;
Suh, Y.; Cho, H.; Oh, U.; Kim, H.; Joo, Y. H.; Shin, S. S.;
Kim, J. K.; Jeong, Y. S.; Koh, H.; Park, Y.; Jew, S.
Bioorg. Med. Chem. Lett. 2005, 15, 631; (b) Jetter, M. C.;
Youngman, M. A.; McNally, J. J.; Zhang, S.; Dubin, A.
E.; Nasser, N.; Dax, S. L. Bioorg. Med. Chem. Lett. 2004,
14, 3053.
N
N
N
H
Ph
46
a
Agonist
TRPV1 pKb/pIC50
Human
Guinea pig
Rat
9. Doherty, E. M.; Fotsch, C.; Bo, Y.; Chakrabarti, P. P.;
Chen, N.; Gavva, N.; Han, N.; Kelly, M. G.; Kincaid, J.;
Klionsky, L.; Liu, Q.; Ognyanov, V. I.; Tamir, R.; Wang,
X.; Zhu, J.; Norman, M. H.; Treanor, J. J. S. J. Med.
Chem. 2005, 48, 71.
Capsaicin
Acid (pH 5.3)
8.7
8.1
8.4
Not tested
8.4
7.6
a data given are pKb with capsaicin and pIC50 with acid as agonists,
respectively.
10. (a) Swanson, D. M.; Dubin, A. E.; Shah, C.; Nasser, N.;
Chang, L.; Dax, S. L.; Jetter, M.; Breitenbucher, J. G.;
Liu, C.; Mazur, C.; Lord, B.; Gonzales, L.; Hoey, K.;
Rizzolio, M.; Bogenstaetter, M.; Codd, E. E.; Lee, D. H.;
Zhang, S.; Chaplan, S. R.; Carruthers, N. I. J. Med. Chem.
2005, 48, 1857; (b) Tafesse, L.; Sun, Q.; Schmid, L.;
Valenzano, K. J.; Rotshteyn, Y.; Su, X.; Kyle, D. J.
Bioorg. Med. Chem. Lett. 2004, 14, 5513; (c) El Kouhen,
R.; Surowy, C. S.; Bianchi, B. R.; Neelands, T. R.;
McDonald, H. A.; Niforatos, W.; Gomtsyan, A.; Lee, C.;
Honore, P.; Sullivan, J. P.; Jarvis, M. F.; Faltynek, C. R.
J. Pharmacol. Exp. Ther. 2005, 314, 400.
guinea pig and dog liver microsomes and a P450 inhibi-
tion profile with IC50 values > 18 lM at five major hu-
man isoforms (1A2, 2C9, 2C19, 2D6 and 3A4).
Compound (46) was also evaluated in a model of
Freund’s Complete Adjuvant (FCA) induced inflamma-
tory hyperalgesia in the guinea pig.18 One hour after
dosing at 30 mg/kg sc, (46) gave 32% reversal of
mechanical hyperalgesia.19
In summary, early lead optimisation chemistry around
the HTS lead (3) led to the identification of series of
N-tetrahydroquinolinyl, N-quinolinyl and N-isoquinoli-
nyl carboxamides which showed excellent antagonist
potency versus capsaicin at recombinant human
TRPV1. A key exemplar from the N-quinolinyl series,
(46),20 also showed similar levels of potency at rat and
guinea pig receptors. Furthermore, (46) possessed excel-
lent potency versus acid at human and rat TRPV1 recep-
tors and has been used as a tool compound to
demonstrate activity in a model of inflammatory pain.
11. Gunthorpe, M. J.; Rami, H. K.; Jerman, J. C.; Smart, D.;
Gill, C. H.; Soffin, E. M.; Luis Hannan, S.; Lappin, S. C.;
Egerton, J.; Smith, G. D.; Worby, A.; Howett, L.; Owen,
D.; Nasir, S.; Davies, C. H.; Thompson, M.; Wyman, P.
A.; Randall, A. D.; Davis, J. B. Neuropharmacology 2004,
46, 133.
12. All new compounds gave satisfactory 1H NMR and/or
mass spectral data.
13. All pKb values represent means from at least three
independent experiments with SD 6 0.3 in all cases.
14. Typical procedure:
A
mixture of aminoquinoline
(0.5 mmol), 4-biphenylcarboxylic acid (0.75 mmol),
EDCI–HCl (0.75 mmol) and DMAP (0.075 mmol) in
DCM (3 ml) was stirred at room temperature for 24 h.
Aqueous work-up followed by column chromatography
on silica gave the desired product.
References and notes
15. Palmer, M. H. J. Chem. Soc. 1962, 3645.
1. (a) Szallasi, A.; Blumberg, P. M. Pharmacol. Rev. 1999, 51,
159; (b) Cortright, D. N.; Szallasi, A. Eur. J. Biochem.
2004, 271, 1814.
2. Bley, K. R. Expert Opin. Investig. Drugs 2004, 13, 1445.
3. Rami, H. K.; Gunthorpe, M. J. Drug Discov. Today:
Therapeutic Strategies 2004, 1, 97.
4. Bevan, S.; Hothi, S.; Hughes, G.; James, I. F.; Rang, H.
P.; Shah, K.; Walpole, C. S.; Yeats, J. C. Br. J. Pharmacol.
1992, 107, 544.
5. Gunthorpe, M. J.; Rami, H. K.; Jerman, J. C.; Smart, D.;
Gill, C. H.; Soffin, E. M.; Luis Hannan, S.; Lappin, S. C.;
Egerton, J.; Smith, G. D.; Worby, A.; Howett, L.; Owen,
D.; Nasir, S.; Davies, C. H.; Thompson, M.; Wyman, P.
A.; Randall, A. D.; Davis, J. B. Neuropharmacology 2004,
46, 133.
6. Rami, H. K.; Thompson, M.; Wyman, P.; Jerman, J. C.;
Egerton, J.; Brough, S.; Stevens, A. J.; Randall, A. D.;
Smart, D.; Gunthorpe, M. J.; Davis, J. B. Bioorg. Med.
Chem. Lett. 2004, 14, 3631.
7. (a) Lee, J.; Kim, S. Y.; Lee, J.; Kang, M.; Kil, M.; Choi,
H.; Jin, M.; Wang, Y.; Toth, A.; Pearce, L. V.; Lundberg,
D. J.; Tran, R.; Blumberg, P. M. Bioorg. Med. Chem.
2004, 12, 3411; (b) Park, H.; Choi, J.; Choi, S.; Park, M.;
16. A solution of (10) (2.20 g) in toluene (300 ml) was treated
with DDQ (5.88 g) and stirred for 1.5 h at 100 °C. The
cooled mixture was filtered, concentrated and purification
of the residue by column chromatography on silica eluting
with an ethyl acetate/petroleum ether gradient gave (27)
(1.75 g, 81%).
17. Austin, N. E.; Baldwin, S. J.; Cutler, L.; Deeks, N.; Kelly,
P. J.; Nash, M.; Shardlow, C. E.; Stemp, G.; Thewlis, K.;
Ayrton, A.; Jeffrey, P. Xenobiotica 2001, 31, 677.
18. Walker, K. M.; Urban, L.; Medhurst, S. J.; Patel, S.;
Panesar, M.; Fox, A. J.; McIntyre, P. J. Pharmacol. Exp.
Ther. 2003, 304, 56.
19. Compound (46) significantly reversed FCA-induced
hyperalgesia by 32 9% compared to the vehicle reversal
of 8 3%. *P < 0.05 ANOVA followed by post hoc LSD
test comparing to vehicle response.
20. Characterising data for (46): 1H NMR (400 MHz,
CDCl3) d (ppm): 9.23 (1H, d, J 2.2 Hz), 8.92 (1H, dd,
J 4.2, 1.6 Hz), 8.33 (1H, dd, J 8.3, 2.3 Hz), 8.23 (1H, s),
8.15, (2H, m), 8.08 (3H, m), 7.90 (1H, d, J 8.3 Hz), 7.87
(1H, d, J 8.9Hz), 7.50 (3H, m), 7.38 (1H, dd, J 8.2,
4.2 Hz).