1662
L. S. Silverman et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1659–1662
Table 3. Receptor affinity of C-8 aryl analogs
Acknowledgments
NH2
We thank Dr. William Greenlee for his support of this
work. We also thank Professor Pier Giovanni Baraldi
et al. for providing us with compounds 18–20 which
were synthesized according to Gatta F. et al. Eur.
J. Med. Chem. 1993, 28, 569.
N
N
N
N
O
Aryl
O
N
N
N
N
Compound
Aryl
A2A Ki (nM)
A1/A2A
669
O
27
0.9
References and notes
39
40
41
42
43
44
45
3.7
2.0
91
83
1. Fredholm, B. B.; Abbracchio, M. P.; Burnstock, G.; Daly,
J. W.; Harden, T. K.; Jacobson, K. A.; Legg, P.; Williams,
M. Pharmacol. Rev. 1994, 46, 143.
2. Svenningsson, P.; Le Moine, C.; Fisone, G.; Fredholm, B.
B. Prog. Neurobiol. 1999, 59, 355.
3. Olah, M.; Stiles, G. L. Pharmacol. Ther. 2000, 85, 55.
4. (a) Shiozaki, S.; Ichikawa, S.; Nakamura, J.; Kitamura, S.;
Yamada, K.; Kuwana, Y. Psychopharmacology 1999, 147,
90; (b) Shiozaki, S.; Ichikawa, S.; Nakamura, J.; Kuwana,
Y. In Effects of Adenosine Receptors; Kase, H., Richard-
son, P. J., Jenner, P., Eds.; Academic Press: New York,
1999; pp 193–210.
5. Aoyama, S.; Kase, H.; Borreli, E. J. Neurosci. 2000, 20,
5848.
6. Ognini, E.; Fredholm, B. B. Trends Pharmacol. Sci. 1996,
17, 364.
7. Kanda, T.; Jackson, M. J.; Smith, L. A.; Pearce, R. K. B.;
Nakamura, J.; Kase, H.; Kuwana, Y.; Jenner, P. Exp.
Neurol. 2000, 162, 321.
8. (a) Baraldi, P. G.; Cacciari, B.; Romagnoli, R.; Spalluto,
G.; Monopoli, A.; Ongini, E.; Varani, K.; Borea, P. A.
J. Med. Chem. 2002, 45, 101; (b) Baraldi, P. G.; Cacciari,
B.; Spalluto, G.; Bergonzoni, M.; Dionosotti, S.; Ongini,
E.; Varani, K.; Borea, P. A. J. Med. Chem. 1998, 41, 2126;
(c) Baraldi, P. G.; Cacciari, B.; Spalluto, G.; Borioni, A.;
Viziano, M.; Dinisotti, S.; Ongini, E. Curr. Med. Chem.
1995, 2, 707; (d) Vu, C. B.; Pan, D.; Peng, B.; Sha, L.;
Kumaravel, G.; Jin, X.; Phadke, D.; Engebr, T.; Huang,
C.; Reilly, J.; Tam, S.; Petter, R. C. Bioorg. Med. Chem.
Lett. 2004, 14, 4831; (e) Gatta, F. et al. Eur. J. Med.
Chem. 1993, 28, 569; (f) Yao, G. et al. Bioorg. Med. Chem.
Lett. 2005, 15, 511.
F
F
9.3
15
CF3
CH3
10.0
20.5
12.6
89.7
181
76
N
108
17
O
N
Table 3 shows the results of the SAR where the N-3 [4-
(2-methoxyethoxy)-phenyl]-1-piperazinyl-4-ethyl moiety
is fixed and the C-8 2-furanyl moiety has been replaced
with various substituted aryl groups. Compared to the
C-8 2-furanyl series, in general the C-8 substituted aryl
derivatives are less potent and selective. Compounds
39 and 40 (phenyl and 3-fluorophenyl) retain good bind-
ing affinity but selectivity against A1 is reduced 7-fold.
The 2-substituted phenyl and pyridinyl ring derivatives
(41–45) are 9- to 90-fold less potent and 4- to 40-fold less
selective than antagonist 27.
9. Zocchi, C.; Ongini, E.; Conti, A.; Monopoli, A.; Negretti,
A.; Baraldi, P. G.; Dionisotti, S. J. Pharmacol. Exp. Ther.
1996, 276, 398.
10. Compound 27: 1H NMR (DMSO-d6,400MHz): d 2.58 (br
s, 4H), 2.75 (t, 2H), 2.95 (br s, 4H), 3.26 (s, 3H), 3.58 (m,
2H), 3.96 (m, 2H), 4.27 (t, 2H), 6.70 (dd, 1H), 6.76–6.84
(m, 4H), 7.22 (m, 1H), 7.78 (br s, 2H), 7.92 (s, 1H), 8.05 (s,
1H).
In summary, we have identified 3-substituted-8-aryl-3H-
[1,2,4]-triazolo[5,1-i]purin-5-amines, a novel series of
adenosine A2A receptor antagonists which display excel-
lent binding affinity and selectivity over the A1 AR.
Most of the N-3 substituted aryl piperazine and piperi-
dine analogs demonstrate in vitro A2A receptor binding
affinity (Ki < 1 nM) and A1 receptor selectivity (A1/
A2A = 300–1700) profiles superior to those of SCH
58261. In addition, compound 27 has demonstrated
superior PK profiles at an oral dose of 3.0 mg/kg
(AUC = 524 ng h/mL) in addition to exhibiting in vivo
activity at 3 mg/kg at 1 and 4 h (80% and 50%) as well
as at 1 mg/kg at 1 and 4 h (55% and 50%) in the rat cat-
alepsy model.13 All studies were carried out in accor-
dance with the National Institute of Health Guide for
the Care and Use of Laboratory Animals.
11. Adenosine A2A and A1 binding assays: [3H]SCH-58261
and [3H]DPCPX binding assays for adenosine A2A and A1
receptors, respectively, were performed as described
previously.12
12. (a) Dionisotti, S.; Ongini, E.; Zocchi, C.; Kull, B.; Arslan,
G.; Fredholm, B. B. Br. J. Pharmacol. 1997, 121, 353; (b)
Klotz, K.-N.; Hessling, J.; Hegler, J.; Owman, C.; Kull,
B.; Fredholm, B. B.; Lohse, M. Naunyn-Schmiedeberg’s
Arch. Pharmacol. 1997, 357, 1.
13. (a) Matasi, J. J.; Caldwell, J. P.; Zhang, H.; Fawzi, A.;
Cohen-Williams, M. E.; Varty, G. B.; Tulshian, D. B.
Bioorg. Med. Chem. Lett. 2005, 15, 3670; (b) Matasi, J. J.;
Caldwell, J. P.; Zhang, H.; Fawzi, A.; Higgins, G. A.;
Cohen-Williams, M. E.; Varty, G. B.; Tulshian, D. B.
Bioorg. Med. Chem. Lett. 2005, 15, 3675.