5692
K. S. Gudmundsson et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5689–5692
imidazo[1,2-a]pyridines.12 Here, the pyrazolo[1,5-c]pyrimidine
series turned out to be a viable alternative to the pyrazolo[1,5-
a]pyridines, showing similar anti-HSV activity and cytotoxicity
profile. Furthermore a number of the pyrazolo[1,5-c]pyrimidines
showed similar or better anti-HSV activity than the current gold
standard, acyclovir. The pyrazolo[1,5-c]pyrimidines are also
slightly less lipophilic than the corresponding pyrazolo[1,5-a]pyri-
dines. The pyrazolo[1,5-a]pyrimidines appear to have a diminished
potency and smaller selectivity index (more cytotoxicity) than the
pyrazolo[1,5-c]pyrimidines and pyrazolo[1,5-a]pyridines. Finally,
the pyrazolo[1,5-a][1,3,5]triazines have demonstrated similar lev-
els of antiviral activity to 1 however the large molecular weight
and high lipophilicity of compound 54 makes it unattractive for
further SAR studies. Finally, evidence of oral bioavailability for
compound 11 suggests the pyrazolo[1,5-c]pyrimidine series has
the potential for further optimization and development as an oral
antiherpetic.
NH
N
NH
N
N
N
N
N
N
N
a
S
S
48
52
Br
NH
NH
N
N
N
N
N
N
N
N
N
F
S
N
H
53
54
b
c
N
N
H
Scheme 5. Reagents and conditions: (a) NBS, CH2Cl2, rt, 30 min (82%); (b) 38,
PdCl2(PPh3)2, Na2CO3, DMF, 100 °C, 12 h (33%); (c) cyclopentylamine (neat) in
pressure vessel, 160 °C, 24 h (34%).
Acknowledgements
We thank Connie J. Sexton and Dean W. Selleseth for antiviral
data.
tylamine displacement of the fluorine in 53 also resulted in dis-
placement of the thiomethyl group, thus giving the di-cyclopen-
tylamino substituted derivative 54.
Anti-HSV activity for pyrazolotriazines 51 and 54 is shown in
Table 2. Pyrazolotriazine 51 is about 10-fold less potent than the
corresponding pyrazolopyridine (55). However, the 5,7-di-cyclo-
pentylamino substituted derivative 54 showed very good anti-
HSV activity (similar activity to the analogous pyrazolopyridine
56). Unfortunately, as compound 54 also has significantly in-
creased molecular weight compared to alternative compounds
with similar anti-HSV activity (such as 11) we decided not to pro-
gress the pyrazolotriazines further.
Compound 11 was chosen for PK studies because of its potent
anti-HSV activity. It was dosed in Sprague–Dawley rats at 1 mg/
kg both iv and po. The concentration versus time curves are
shown in Figure 2. A moderate clearance of 24.1 ml/min/kg was
observed along with a 2.5 h half life and volume of distribution
of 1.2 L/kg. The oral bioavailability was 24% with a Cmax of
References and notes
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Previously, we had shown that the pyrazolo[1,5-a]pyridines in
general showed better antiviral activity than the corresponding
Rat Plasma Profile for 11
10.00
11 IV
11 PO
1.00
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0.10
0.01
0
5
10
15
20
Hours
Figure 2. Rat pk profile for 11.