514
G. Yao et al. / Bioorg. Med. Chem. Lett. 15 (2005) 511–515
Table 3. Summary of efficacy data in rodent models of ParkinsonÕs
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diseasea
NH2
O
N
N
N
N
R
Compd
Mouse
Rat
Rat
7. (a) Shimada, J.; Koike, N.; Nonaka, H.; Shiozaki, S.;
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catalepsy
PO (ED50
(mg/kg)
catalepsy
PO (ED50
(mg/kg)
6-hydroxydopamine
PO (MED)
(mg/kg)
)
)
8
3
3
3
3
>3
NT
NT
NT
3
9
10
NT
3
12
14
3
>3
3
NT
3
NT
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23
24
>10
10
1
NT
1
NT
3
KW-6002
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Wenk, P.; Friedmann, R. C.; Atkins, C.; Warren, V.;
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a For the mouse catalepsy study, male CD-1 mice (25–30 g) were
injected subcutaneously with 3 mg/kg of haloperidol in order to
induce catalepsy. For the rat catalepsy study, male Sprague–Dawley
rats (225–275 g) were treated with haloperidol (1 mg/kg sc) in order
to induce catalepsy. ED50 refers to the minimum dose that causes at
least a 50% reduction in catalepsy. For the 6-hydroxydopamine
studies, male Sprague–Dawley rats with a unilateral 6-hydroxydop-
amine lesion of the nigrostriatal pathway were given test compound
30 min before a subthreshold dose of L-dopa (3.7 mg/kg ip), and
rotational behavior was measured for 2 h. MED refers to the mini-
mum dose that caused a significant increase in rotational behavior. In
all of these studies, test compounds, formulated as the hydrochloride
salts, were dissolved in saline and administered by oral gavage.
Details regarding the mouse catalepsy model can be found in Refs.
11e,17a,b.
11. (a) Peng, H.; Kumaravel, G.; Yao, G.; Sha, L.; Wang, J.;
Vlijmen, H. V.; Bohnert, T.; Huang, C.; Vu, C. B.;
Ensinger, C. L.; Chang, H.; Engber, T. M.; Whalley, E. T.;
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Shields, P.; Peng, B.; Kumaravel, G.; Jin, X.; Phadke, D.;
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Med. Chem. Lett. 2004, 14, 4835; (c) Vu, C. B.; Pan, D.;
Peng, B.; Sha, L.; Kumaravel, G.; Jin, X.; Phadke, D.;
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Bioorg. Med. Chem. Lett. 2004, 14, 4831; (d) Vu, C. B.;
Pan, D.; Peng, B.; Kumaravel, G.; Smits, G.; Jin, X.;
Phadke, D.; Engber, T.; Huang, C.; Reilly, J.; Tam, S.;
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Jin, X.; Phadke, D.; Engber, T.; Huang, C.; Reilly, J.;
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12. Harada, H.; Asano, O.; Hoshino, Y.; Yoshikawa, S.;
Matsukura, M.; Kabasawa, Y.; Niijima, J.; Kotake, Y.;
Watanabe, N.; Kawata, T.; Inoue, T.; Horizoe, T.;
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13. Sato, N. J. Heterocycl. Chem. 1982, 19, 673.
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15. Typical synthetic procedure for 16 and analogs thereof: A
solution of 4-acetylpyridine (1 equiv) in dry THF under
argon was cooled to 0 °C with an ice bath. Ethynylmag-
nesium chloride (2.5 equiv) was added dropwise, and the
solution was stirred at room temperature for 1–3 h. The
reaction was quenched by the addition of a saturated
ammonium chloride solution in water, and the THF was
evaporated in vacuo. The residue was then extracted with
ethyl acetate and the combined organic extracts were dried
over magnesium sulfate, and concentrated in vacuo to
yield the desired propargyl alcohol, which was used in the
coupling reaction without further purification.
12 and 23 were further tested in the 6-hydroxydopamine
rat model. Among them, compound 12 is particularly
promising, showing oral activity at 3 mg/kg. In contrast,
compound 23, which has a cyclo alkyl substituent, did
not exhibit activity at 3 mg/kg.
In summary, we have demonstrated for the first time
that 2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine
core, when coupled with branched propargyl alcohols,
can afford potent adenosine A2A receptor antagonists
with both in vitro and in vivo activities. Selected com-
pounds from this series have been shown to be orally ac-
tive in three different rodent models of ParkinsonÕs
disease (e.g., compound 12).
References and notes
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6. (a) Petzer, J. P.; Steyn, S.; Castagnoli, K. P.; Chen, J.-F.;
Schwarzschild, M. A.; Van der Schyf, C. J.; Castagnoli, N.
To a solution of 6-bromo-2-furan-2-yl-1,2,4triazolo[1,5-
a]pyrazin-8-ylamine (1 equiv) and the above prepared
alkyne (2 equiv) in a 1:1 mixture of DMF and TEA were
added copper(I) iodide (20 mol %) and palladium (0)
catalyst (15 mol %). The reaction vessel was degassed and
heated at a 100 °C for 6 h. After cooling, water was added
and the residue was extracted with ethyl acetate. The