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Table 6
Rat PK and tissue distribution of 12
Mouse
IV/oral dose (mg/kg)
CL (mL/min/kg)
Oral t1/2 (h)
Oral plasma Cmax (nM)
F (%)
Brain/plasma 1 h
12
Rat
12
5/10
69
0.3
Oral t1/2 (h)
0.7
5009
5
F (%)
83
—
IV/oral dose (mg/kg)
2/10
CL (mL/min/kg)
65
Oral plasma Cmax (nM)
2978
Brain/plasma 1 h
1.2
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assay protocol please refer to Ref. 11a.
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substituted compounds in Table 5. Dose–response studies were
carried out with active compounds and revealed that 12, 14, and
40 were all quite potent in reversing catalepsy in mice. We did
not investigate 25–27 further with pharmacokinetic (PK) or tissue
distribution studies, but in general 25–27 had moderate metabolic
stability and similar protein binding properties compared to the
three active compounds.
Compound 12 showed good plasma levels (Cmax = 5.0 lM) in
mice but suffered from a very short half-life and poor bioavailablity
(Table 6). A duration of action in the mouse catalepsy model
showed that the compound was only able to reverse catalepsy at
the 0.5 and 1 h time points, but not at 2 or 4 h, confirming the re-
sults obtained in the PK study. Further characterization of 12 in a
rat PK/tissue distribution study showed that the compound had
good oral exposure (Cmax ꢀ 3
lM) and good bioavailability, but suf-
fered from high clearance and a short half-life (Table 6). The com-
pound also had a brain to plasma ratio of 1.2 at 1 h post-dosing.
Compounds 14 and 40 had similar liabilities in both mice and rats
including high clearance, short half-life, and short duration of ac-
tion in mouse catalepsy.
In summary, we have shown that benzyl substituted thieno[2,3-
d]pyrimidines are potent A2A antagonists having good in vivo effi-
cacy in the mouse catalepsy model, but in general these com-
pounds suffer from a short half-life, limiting their use as a
potential therapeutic for PD. The benzyl thieno[2,3-d]pyrimidines
had good in vitro potency when substituted with methylfuran
and 3-cyanophenyl as previously reported, but several new 5-
and six-membered heterocycles (25–27 and 53–54) have been
identified that maintain in vitro potency.
14. A 300 mg/kg dose of L-DOPA was used as the positive control in the mouse
catalepsy studies.
References and notes
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