M. Billah et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1617–1619
Table 1. 2-Substituted quinoline-5-carboxamidesa
1619
5
6
R
R1
PDE4 IC50
RBAIC 50
PDE 4:RBAPDE 3 (%)
D4418
4a
4b
4c
4d
4e
4f
4g
H
CH3
CN
H
CF3
H
H
0.17
0.088
0.70
0.21
0.051
0.043
0.44
0.18
0.21
0.53
0.32
1.19
16.28
1.31
0.66
0.57
0.29
0.22
1.5
10
0.074
0.043
0.16
0.077
0.0753
1.5
21
38
12
15
35
27
30
22
H
CH2CH3
H
H
H
H
H
CH2CH3
C(O)CH3
C(OH)CH3
C(NOCH3)CH3
0.79
0.14
4h
aValues are shown as IC50 (mM) or per cent inhibition at 20 mM and are the means of at least two experiments. RBA, rolipram binding assay. PDE4
was obtained from human U937 cells, rolipram binding protein was obtained from rat brain tissues, and PDE3 was obtained from human platelets.
In conclusion, 4d is a novel, potent and selective inhi-
bitor of PDE4. Compared with D4418, it had an
improved plasma half life in vivo when dosed orally to
guinea pigs, and significantly improved activity in a
guinea pig lung eosinophilia model. Further studies on
compounds in this series will be reported in due course.
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Figure 2. Inhibition of guinea pig lung eosinophilia by oral dosing of
4d at 1, 3 and 10 mg/kg.