5110
Y. Takano et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5107–5111
Table 3. Pharmacological data of substituted 7-imidazolyl quinoxalinecarboxylic acid derivative
Compd
AMPA-R affinity10a
(Ki, nM)
Selectivity11
AMPA-R
antagonism10b
(DC potential)
Stability
for light12
Protective effects in
focal ischemia model13,14
(dose; mg/kg/h for 4h, iv)
ꢀ
ꢁ
NMDA À R
AMPA À R
YM-90K
YM-872
100
62
430
240
(+)
(+)
(+)
(+)
(À)
(À)
(À)
(+)
2.8 (15)
0.5 (30)
3.0 (2.5)
2.7 (2.5)
1
9k
22
16
>400
>630
8.29mg/mL).15 These characteristics of 9k suggest its
suitability as an injectable formulation for the treatment
of acute cerebral ischemia. It is noteworthy that the
photostability and receptor selectivity of 9k are superior
to those of 1, even though both compounds possess a
quinoxalinecarboxylic acid nucleus. It seems that intro-
duction of a trifluoromethyl group at the C-6 position
not only imparts potent AMPA-R affinity and high
selectivity but also contributes to good physicochemical
properties and to therapeutic efficacy in an animal
model. Consequently, we believe that the trifluoro-
methyl-substituted quinoxalinecarboxylic acid 9k is a
useful structure for scaled-up chemical synthesis and
pre-formulation studies for parenteral delivery.
6. (a) Shishikura, J.; Tsukamoto, S.; Inami, H.; Fujii, M.;
Okada, M.; Sasamata, M.; Sakamoto, S. WO 9610023
Chem. Abstr. 1996, 125, 114689; (b) Kawasaki-Yatsugi, S.;
Yatsugi, S.; Takahashi, M.; Toya, T.; Ichiki, C.; Shimizu-
Sasamata, M.; Yamaguchi, T.; Minematsu, K. Brain. Res.
1998, 793, 39.
7. (a) Ottow, E.; Huth, A.; Kruger, M.; Schneider, H. H.;
Neuhaus, R.; McDonald, F.; Lofberg, B.; Turski, L.
Biomed. Health Res. 2001, 45, 329; (b) Turski, L.; Huth,
A.; Sheardown, M.; McDonald, F.; Neuhaus, R.; Schnei-
der, H. H.; Dirnagl, U.; Wiegand, F.; Jacobsen, P.; Ottow,
E. Proc. Natl. Acad. 1998, 95, 10960.
8. Takano, Y.; Shiga, F.; Asano, J.; Ando, N.; Uchiki, H.;
Anraku, T. Bioorg. Med. Chem. Lett. 2003, 13, 3521.
9. Bigge, C. F.; Boxer, P. A.; Ortwine, D. F. Curr. Pharm.
Des. 1996, 2, 397; Bigge, C. F.; Nikam, S. S. Exp. Opin.
Ther. Patents 1997, 7, 1099.
10. (a) Johansen, T. H.; Drejer, J.; Watjen, F.; Nielsen, E. O.
Eur. J. Pharmacol. Mol. Pharmacol. Sect. 1993, 246, 195;
(b) Neil, L. H.; Michael, A. S. Br. J. Pharmacol. 1985, 84,
381.
In conclusion, molecular design of novel AMPA-R
antagonists with
a
6-trifluoromethylquinoxaline-
carboxylic acid nucleus led to compounds with good
biological activity and physicochemical properties.
Investigation of structure–activity relationships and sub-
stance properties identified compound 9k (KRP-199)16
for further study. Finally, this research allowed us to
develop superior AMPA-R antagonist candidates by
replacing the 6-nitro group on the quinoxalinecarboxylic
acid nucleus by a 6-trifluoromethyl group and exploited
a new strategy to develop novel AMPA-R antagonists.
11. Murphy, D. E.; Hutchison, A. J.; Hurt, S. D.; Williams,
M.; Sills, M. A. Br. J. Pharmacol. 1988, 95, 932.
12. Stability test: All test compounds were dissolved in 0.1M
sodium phosphate buffer (pH7.4). Residual ratios were
determined by HPLC analysis after irradiation for 3h
under a fluorescent light (7000Lx) in a clear glass bottle.
In the tables, (+) denotes more than 95% residual
compound ratio, and (À) denotes less than 95%.
13. Tamura, A.; Graham, D. I.; McCulloch, J.; Teasdale, G.
M. J. Cereb. Blood Flow Metab. 1981, 1, 53.
14. Evaluation of the rat focal ischemia model: After 24h of
MCA occlusion as described by Tamura et al., brains were
removed and sliced into five coronal (2-mm thick) sections
with the use of a rat brain matrix (a manual slicer). Slices
were placed in 2% (w/v) triphenyltetrazolium chloride
(TTC) solution, and then in 10% (v/v) phosphate-buffered
formalin. Tissue damage (areas not stained with TTC) was
scored on a four-point scale (see figure A). Each test
compound was administered by continuous iv infusion for
4h, starting immediately after occlusion of the MCA.
Control rats received saline only, and their four-point
scale value was less than 1.0. As comparable compounds,
Acknowledgements
We are grateful to Mr. K. Fukuchi for running the radi-
oligand-binding assay, and we would like to thank Dr.
K. Obi and Dr. T. Ishizaki in Kyorin Pharmaceutical
Co. Ltd for helpful discussion.
References and notes
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